Role of MicroRNAs in Cancers [1st ed. 2022] 9789811691850, 9789811691867, 9811691851

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DKV Prasad · Pinninti Santosh Sushma   Editors

Role of MicroRNAs in Cancers

Role of MicroRNAs in Cancers

DKV Prasad • Pinninti Santosh Sushma Editors

Role of MicroRNAs in Cancers

Editors DKV Prasad Department of Biochemistry NRI Institute of Medical Sciences Visakhapatnam, Andhra Pradesh, India

Pinninti Santosh Sushma Biomedical Sciences Division College of Community Health Sciences, University of Alabama Tuscaloosa, AL, USA

ISBN 978-981-16-9185-0 ISBN 978-981-16-9186-7 https://doi.org/10.1007/978-981-16-9186-7

(eBook)

# The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

This book is dedicated— To my father, Sri Thamma Rao who left the world after a lifetime of leaving smiles on the faces of those around him and who taught me to be an independent and determined person. I have no doubt that without him I would not be the person I am today. —Dr. DKV Prasad

Preface

Development of cancer may be due to genetic and epigenetic changes which require activation of oncogenes and inactivation of tumor suppressor genes depending on their molecular mechanisms. Although cancer has multifaceted etiology, these predisposing factors lead to a precarious condition in which the personal genomics plays a vital role in predisposing individuals to cancer. Despite significant advances in research, still the management of cancer is dismal. Primary prevention appears as a challenging goal, with a possibility for the secondary prevention like early detection of the disease by identifying the molecular targets. These molecular targets could lie in the signaling pathway or in the tumor cells or their receptors. Since the last decade, small non-coding RNAs called miRNAs have attracted much attention of molecular oncologists. These are a new class of short non-protein-coding, endogenous, small RNAs, functioning as post-transcriptional regulators that bind to the target messenger RNA most commonly resulting in gene silencing. They are involved in every complex process from cell growth to apoptosis which is indicative of their importance in cell function. Several reports indicate overexpressed miRNAs may function as oncogenes and promote cancer development by negatively regulating tumor suppressor genes and/or genes that control cell differentiation or apoptosis. About 5300 human genes have been implicated as targets for miRNAs, making them one of the most abundant classes of regulatory genes in humans. MiRNAs recognize their target messenger RNAs based on sequence complementarity and act on them to cause the inhibition of protein translation by degradation of mRNA. Tumor tissues often exhibit significantly reduced expression levels of mature miRNAs. Different mechanisms for the aberrant expression of miRNA include genetic alterations or single nucleotide polymorphism (SNP), epigenetic silencing of the target gene, or defects in the miRNA expression. The scope of this volume is to provide the scientists and other research professionals’ exceptional information regarding microRNAs role in cancers and helping them to investigate and develop advanced strategies for cancer treatment. Visakhapatnam, Andhra Pradesh, India Tuscaloosa, Alabama, USA

DKV Prasad Pinninti Santosh Sushma

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Acknowledgments

Without the experiences and support from my well-wishers, this book would not exist. You have given me the opportunity to lead a great group of individuals—to be a leader of great leaders is blessed place to be. Thank you to Dr. Sushma, Dr. Imran, Dr. Manjari, Dr. Sitara, Dr. Kilari, and Dr. Sabeena. Having an idea and turning it into a book is as hard as it sounds. The experience is both internally challenging and rewarding. I especially want to thank publishing team, who helped make this happen. Special thanks are also due to my wife, Dr. Prabhavathi, whose comments, insights, and suggestions were invaluable; my daughter, Sai Susmitha, who is a constant source of energy, support, and inspiration.

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Contents

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Introduction to MicroRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DKV Prasad and Pinninti Santosh Sushma

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MicroRNAs and Cancer Signaling Pathways . . . . . . . . . . . . . . . . . . K. Sri Manjari, Srilekha Avvari, Imran Ali Khan, and DKV Prasad

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Role of MicroRNAs in Cell Growth Proliferation and Tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Srilekha Avvari, DKV Prasad, and Imran Ali Khan

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The Impact of MicroRNAs in Cell Adhesion and Tumour Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gaurav Singh, DKV Prasad, Pinninti Santosh Sushma, and K. Sri Manjari

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Oxidative Stress Modulation with MicroRNAs in Cancers . . . . . . . . Srilekha Avvari, M. Rishitha, K. Sri Manjari, Subhadra Poornima, and Imran Ali Khan

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MicroRNAs Targeting Tumor Microenvironment and Immune Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sitara Roy and DKV Prasad

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Role of Circulating MicroRNAs in Prognosis and Diagnosis of Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 DKV Prasad, Vurla Prabhavathi, Pinninti Santosh Sushma, M. Sai Babu, P. Aruna, and Imran Ali Khan

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Role of MicroRNAs in Cancer Drug Resistance . . . . . . . . . . . . . . . . 133 Kondapalli N. Babu and Sreenivasulu Kilari

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Role of Dietary Compounds in Altered MicroRNA Expression and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Himaja Nallagatla, DKV Prasad, and Pinninti Santosh Sushma

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Computational Approaches for MicroRNA Studies . . . . . . . . . . . . . 165 Sabeena Mustafa, Maya Madhavan, Pinninti Santosh Sushma, and DKV Prasad

Editors and Contributors

About the Editors DKV Prasad is an Associate Professor in the Department of Biochemistry and In-charge, Central Research Laboratory, NRI Institute of Medical Sciences at Visakhapatnam, Andhra Pradesh. Dr. Prasad obtained his medical degree from Nagarjuna University, Andhra Pradesh, MSc (Psychology) from Madras University, MSc (Medical Biochemistry), and PhD (Medical Biochemistry) from Dr. NTR University of Health Sciences, Vijayawada, Andhra Pradesh. He has more than 25 years of teaching experience in Biochemistry and also mentored medical graduate and post-graduate medical biochemistry students to his credit. His research focused on genetics of idiopathic generalized epilepsy (IGE) and its association with oxidative stress and antiepileptic drug therapy. He successfully published his work in nationally and internationally reputed journals and authored or coauthored few book chapters. He also presented abstracts at various national and international conferences. Dr. Prasad tries to lead by example, promoting honesty, integrity, laboratory safety, and a healthy work-life balance. In the laboratory, he encourages each student to take ownership of their project, providing scaffolding, advice, and troubleshooting when necessary but ultimately letting each person design their own path. He provides opportunities to practice key skills including oral presentations, literature analysis, and scientific writing and encourage participation in conferences, internship experiences, and travel to work with collaborators around the globe. Dr. Prasad has completed the clinical biochemistry degree MIBCB (Member of Indian Board of Clinical Biochemistry), which is empanelled by Quality Council of India (QCI). He is a member of many international scientific societies and organizations. He is a member secretary for Institutional Ethics Committee, NRI Institute of Medical Sciences, Visakhapatnam. He is a reviewer of several international journals and serves as editorial board member for well-reputed international and national journals. Pinninti Santosh Sushma is a postdoctoral fellow at the University of Alabama, Tuscaloosa. Previously, she has completed her PhD from the National Institute of Nutrition. Her work was focused on understanding the role of microRNA in different

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cancers specifically on the mechanisms of microRNAs targeting tumor suppressor genes and DNA methylation patterns. She has published several research articles in national and international journals of high repute.

Contributors Kondapalli N. Babu National Institute of Nutrition, Hyderabad, India Imran Ali Khan Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia Sreenivasulu Kilari Department of Radiology, Mayo Clinic, Rochester, MN, USA Sabeena Mustafa Department of Biostatistics and Bioinformatics, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia Himaja Nallagatla Telangana Social Welfare Residential Degree College, Hyderabad, India Aruna Pitchika Bronxcare Health System, Bronx, NY, USA Subhadra Poornima Department of Genetics and Molecular Medicine, Kamineni Life Sciences, Hyderabad, India V. Prabhavathi Department of Obstetrics and Gynecology, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India M. Rishitha University College for Women, Koti, Osmania University, Hyderabad, India Sitara Roy University of California, San Diego, CA, USA M. Sai Babu K-Genomics, Hyderabad, India Gaurav Singh Department of Biosciences, Universitàdegli Studi di Milano, Milan, Italy K. Sri Manjari Department of Genetics and Biotechnology, University College for Women, Koti, Osmania University, Hyderabad, Telangana, India Avvari Srilekha Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad, India

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Introduction to MicroRNAs DKV Prasad and Pinninti Santosh Sushma

Abstract

MiRNAs are small noncoding RNAs ranging in length from 20 to 22 nucleotides. They are documented to be involved in complex cellular process from cell cycle initiation to apoptosis indicating their importance in cellular functioning. The discovery of lin-4 miRNAs has revolutionized the field of molecular biology. MiRNA has a vital role in proliferation and cellular death. MiRNA expression is abnormal in number of malignancies. The expression of miRNA is well correlated with given type of cancer and its stage and differentiates the tumor from normal tissue. MicroRNAs have vital functions in determining the destiny of cancer stem cells (CSCs). Previous research has found that miRNAs can control the process of angiogenesis and survival of tumor cell as well. MiRNAs function as oncogenes and tumor suppressor genes depending on the pathway they are involved. The diagnostic potential of miRNAs is overwhelming projecting them as critical players in cancer research. Keywords

MiRNAs · Cancer · MiRNA biogenesis · Oncogenes · Tumor suppressor genes

D. Prasad (*) Department of Biochemistry, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India P. Santosh Sushma Biomedical Sciences Division, College of Community Health Sciences, University of Alabama, Tuscaloosa, AL, USA # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Prasad, P. Santosh Sushma (eds.), Role of MicroRNAs in Cancers, https://doi.org/10.1007/978-981-16-9186-7_1

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1.1

D. Prasad and P. Santosh Sushma

Introduction

The microRNAs (miRNAs) are a class of regulatory noncoding RNAs with sizes ranging from 17 to 25 nucleotides. In the year 1993, the first microRNA, lin-4, was reported by Ambros and Rukvun (Lee et al. 1993). Since then, the miRNA era has expanded by the identification of abundant small RNAs from C. elegans, Drosophila, and human (Lee and Ambros 2001). There is an enormous rise in the number of the miRNAs as well as the associated publications during the last 7 years. Nearly more than 5000 miRNAs from various organisms have been identified and registered in online database so far (miRBase release 10.0, August 2007). Currently, about 533 human miRNAs have been discovered. However, this number is expected to keep increasing. It is believed that about 1000 miRNAs exist from bioinformatic studies (Bentwich et al. 2005). With a few exceptions, the miRNAs are named along with their number. If the miRNAs follow the number in a similar sequence, they are frequently differentiated by an extra letter such as a, b, and c (e.g., miR-125b). The miRNA may appear with different precursor sequences at several genomic loci if they are of identical mature sequence. About one-third of the miRNAs in humans are arranged in structural clusters. A cluster is a single transcription unit in which miRNAs are coordinately regulated. Moreover, 50% of the clusters consist of two or more miRNAs of analogous sequences (Yu et al. 2006). However, identical mature sequences are hardly replicated in a cluster. Such a genomic structure entails the simultaneous representation of comparable miRNAs which might lead to diversification and biological synergies as well. But, the most important thing to know is that not all miRNAs from a single transcription cluster are to be equally expressed, demonstrating that miRNAs are also posttranscriptionally regulated. The generation of the pri-miRNA is the first step in miRNA biogenesis. Generally, the pri-miRNAs’ transcription is done by RNA polymerase II (Cai et al. 2004). Also, a modest number of miRNAs are also produced, primarily from genome repeats from other pathways, for instance, RNA polymerase III transcription of miRNA in Alu repeats (Borchert et al. 2006). The pre-miRNA is further processed by RNase III enzyme, Drosha, and its companion DGCR8 from pri-miRNA (Gregory et al. 2004). A subset of miRNAs (mirtrons) follows a different pathway in which pre-miRNAs are generated as a by-product of a splicing and debranching thereby bypassing the Drosha cleavage (Okamura et al. 2007). The exportin-5 exports the pre-miRNA from the nucleus to the cytoplasm (Lund et al. 2004) and is processed to mature duplex miRNA by Dicer, another RNase III enzyme (Hutvagner et al. 2001). During the formation of a miRNA particle (miRNP), the RNA helicase separates the two strands of the duplex (Salzman et al. 2007) (Fig. 1.1). MiRNAs inhibit target mRNA posttranscriptional expression, through interacting with the 30 UTR. But, the precise method by which miRNAs affect their targets is still unknown (Filipowicz et al. 2008). Most miRNA target sites have numerous mismatches due to unlikely perfect sequence. Previous studies comparing siRNA and miRNA revealed that siRNAs were destabilizing mRNA translated, whereas

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Introduction to MicroRNAs

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Fig. 1.1 The mechanism of miRNA biogenesis

miRNAs were inhibiting the same without altering mRNA levels. As a result, the extent of complementarity between short RNA and target was believed to be a key factor in separating the two systems.

1.2

MiRNA and Cancer

MiRNA has a vital role in proliferation and cellular death. In addition miRNAs are involved in a variety of cell signaling processes such as immune response mediation evaluated in insulin secretion, neurotransmitter synthesis, circadian rhythm, viral replication, and so on. This list is expected to grow as more experimental data becomes available (Calame 2007). MiRNA expression is abnormal in a number of malignancies. The first examples, miR-15a and miR-16-1, were found on chromosome 13q14. This is important because it is a usually deleted area in B-cell chronic lymphocytic leukemia (CLL) and other malignancies (Calin et al. 2002). Simultaneously, it has been observed that expression of these miRNAs is diminished in cancer samples. Microarray technology has facilitated miRNome analysis. Many miRNAs are up- or downregulated in malignant cells vs normal cells. The expression of miRNA is well correlated with given type of cancer and its stage and differentiates the tumor from normal tissue. The miRNome was successfully applied in the primary systemic analysis of majority of cancer samples and

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normal tissues (Lu et al. 2005). The fact that miRNome outperformed the mRNA expression profile in terms of cancer kind and stage energized the authors of these investigations. Hence, miRNome can be recommended as a feasible screening marker for the diagnosis of cancer and its prognosis as well.

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Mechanisms Behind MiRNA Deregulation in Cancers

Chromosomal abnormality is a significant cause of miRNA dysregulation in cancers. It is generally observed that structural chromosomal aberrations such as deletion, amplification, translocation, and so on are frequently associated with neoplasia. According to in silico study, a large proportion of miRNAs are mapped to fragile sites or cancer-related genomic regions in humans and mice. The comparison between array comparative genomic hybridization (CGH) data and expression data of miRNA demonstrates that in various situations, the levels of miRNA are comparable with alterations in genomic loci copy number (Porkka et al. 2007; Rinaldi et al. 2007). Epigenetic factors were known to play a crucial role in miRNA regulation process. Many malignancies have been found to have hypermethylation in promoter region of tumor suppressor genes. Histone modification and gene silence via DNA methylation are intimately connected. CpG islands surrounding several miRNAs were identified using in silico research. Some of the miRNA were upregulated when cells were exposed to the demethylating chemical 5-aza-20 -deoxycytidine due to DNMT (DNA methyltransferase) mutation or HDAC (histone deacetylase) inhibitor therapy. It has been noticed that several miRNAs were inhibited by CpG hypermethylation in malignancies. Hypermethylation of miR-124a is tumor-type specific, as methylation was not found in neuroblastoma. A miRNA’s epigenetic silencing could be tissue specific. MiR-124a is often highly expressed in neuronal tissues; therefore its epigenetically silenced expression in colorectal tumors is not surprising. MiRNAs may be able to prevent CpG methylation. For instance, miR-29 results in a general decrease in DNA methylation, which leads to the derepression of some of the anti-oncogenes (Fabbri et al. 2007). The transcriptional regulation mechanism has been thoroughly described in numerous examples, where miRNAs are tuned by several transcription factors throughout the process of differentiation. Transcription factors can well induce miRNAs by upregulation by activating pri-miRNA transcription. Different transcription factors have a wide range of effects on fundamental biological process. MiRNAs are influenced by processing efficiency and stability of the precursors, as well as the transcription rate. There is frequently a disparity in miRNA mature form expression compared to that of precursors (Mott et al. 2007). A time course experiment after pre-miR-21 induction discovered a delayed kinetics in mature miR-21 accumulation (Loffler et al. 2007). These findings suggest that miRNA processing is critical in determining miRNA expression levels. A thorough data analysis highlights this process in malignancies (Thomson et al. 2006). MiRNA levels in cancer cells are observed to be lower than in nonmalignant tissues. As

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Introduction to MicroRNAs

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indicated by microarray data between mRNA and miRNA, reduction in malignancies is poorly linked to reduced expression of the host gene. Many viruses control carcinogenesis by expressing viral oncogenes or triggering cellular oncogenes via viral DNA incorporation into genomic LMP1, whose overexpression induces detrimental consequences in host cells (Pfeffer et al. 2004). EBV-mediated cellular transformation is aided by EBV miRNAs by lowering the LMP1 level to a nonlethal level (Lo et al. 2007). A viral miRNA, such as that from Kaposi sarcoma-associated herpesvirus (KSHV), can sometimes target the antiangiogenic factor thrombospondin-1 directly (Samols et al. 2007). As a result, these viral miRNAs function as viral oncogenes. The abnormal expression of miRNAs is caused by viral integration near the miRNA. MicroRNAs have vital functions in determining the destiny of cancer stem cells (CSCs) (Lerner and Petritsch 2014). MiRNAs, for instance, miR-296, miR-134, mir-470, and the miR-34 family targeted a variety of genes required for pluripotency as well as activity of stem cell. The let-7, miR-200, and miR-30 families are thought to regulate CSCs of the breast. In breast CSCs, the let-7 family is downregulated in carcinoma of the breast. In addition, let-7 family members have also been linked to breast cancer oncogenesis and metastasis in immunocompromised mice by modulating breast CSCs (Sun et al. 2012). Angiogenesis is required for tumor progression and metastasis, as is well known (Pasquier et al. 2013). Previous research has found that miRNAs can control the process of angiogenesis and survival of tumor cell as well. The miR-17-92 clusters were found to be upregulated in Myc-induced tumors and are overexpressed among RAS cells, promoting angiogenesis in paracrine fashion (Kuhnert and Kuo 2010). MiR-378 inhibits growth and cell survival by targeting EHD1 and ALCAM, respectively, exhibited similar results in ovarian cancer (Chan et al. 2014). Both let-7f and miR-27b overexpression promote angiogenesis (Melo and Kalluri 2012), whereas miR-221 and miR-222 suppress angiogenesis by targeting pro-angiogenic endothelial cell activity in malignancies (Santhekadur et al. 2012). The miR-15-16 repression was associated with advanced stage of colorectal cancer (Xue et al. 2015). EMT has been implicated in progression, metastasis, and invasion of tumor cells, but reverse mesenchymal to epithelial transition activation is essential for metastatic cascade. Epithelial cadherin 1 gene expression (E-cadherin) is required for epithelial cell survival (Liu and Chu 2014). In breast cancer cells, it was observed that a positive association between miR-200 expression and E-cadherin concentration. In renal cells, restoring miR-200 expression is adequate to reverse the transformation (mesenchymal to epithelial). An inverse association is noted between MiR-30 family expression and mesenchymal phenotype in pancreatic epithelial cells (Zhang et al. 2012). EMT is reversed in mesenchymal ovarian cancer cell lines by miR-429 overexpression (Chen et al. 2011). The alterations in miRNA expression can cause a disaster by activating malignant transformation in cells, making cancer cells chemotherapeutic resistant. It goes without saying that understanding these mechanisms will aid in the fight against drug resistance. According to the current data, the miRNA deregulation mechanism includes miRNA minimum regions of deletion, epigenetic control, transcription

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factor, deregulation, and dysregulation of central genes/proteins involved in the synthesis of miRNA and their processing (Calin and Croce 2006). Furthermore, competitive endogenous RNA (ceRNA) binds to miRNA competitively and thereby decrease the amount of intracellular miRNA drastically. Majority of human miRNAs are identified in cancer-related regions (Calin et al. 2004). These genes are more likely to be deleted, translocated, or amplified. Deletions on the 13q14 chromosome, for example, were the most common among chromosomal abnormalities. In majority of chronic lymphocytic lymphoma (CLL) patients, both miRNA-15a and miRNA-16-1 are situated on 13q14 and commonly deleted or downregulated. The miRNA-17-92 family, on the other hand, is found in the 13q31-q32 area. This area has shown amplification in a number of tumors, resulting in raise in the number of mature miRNAs and so boosting oncogenesis (He et al. 2005). Due to the small number of studies, the relationship between drug resistance and its correlation with miRNA dysregulation, gene amplification, and deletion has not been extensively studied. Previous research has linked the prognosis and therapeutic benefit of imatinib on patients with chronic myelocytic leukemia (CML) to miRNA-219-2 and miRNA-199b expression. In CML patients, a decrease in miRNA-199b expression may contribute to imatinib resistance (Joshi et al. 2014). Around 20% of CML patients have gene deletions at translocation breakpoints on the derivative chromosome 9 (der (9) chromosome) (Cohen et al. 2001). MiRNA-21 was upregulated in multiple malignancies and linked to tumor cell resistance. Chaluvally-Raghavan et al. found that miRNA gene amplification is associated with resistance to drugs in tumors (Chaluvally-Raghavan et al. 2014). They discovered that miRNA-569 overexpression was caused, at least in part, by 3q26.2 amplification in a subset of ovarian and breast tumors. In ovary and breast cancer cells, miRNA targeting makes it more susceptible to CDDP by increasing the cellular death. As previously documented, gene amplification promotes upregulation of the miRNA-17-92 family. This is one of the most common causes of increasing treatment resistance in different cancer types. Hayashita et al. discovered that in lung cancer histology, specifically SCLC histology, the miRNA-17-92 cluster, which includes miRNA-17, enhances lung cancer cell proliferation (Hayashita et al. 2005). Most chemotherapeutic agents, such as antimetabolite drugs, work by reducing cell proliferation, thereby promoting apoptosis (Kaufmann and Earnshaw 2000). To some extent, drug-resistant cell lines can tolerate these medications. MiRNAs influence chemoresistance by controlling critical genes in signaling pathways. The phosphatase and tensin homolog (PTEN) can inhibit the P13/AKT signaling pathway, limiting cell growth and inducing apoptosis. PTEN inactivation is linked to oncogenesis and a sequence of miRNAs that regulate PTEN and impact the responsiveness of cancer cells to chemotherapeutic agents. One such example is miRNA-21, which targets PTEN in gastric cancer (Eto et al. 2014) and oral cancer (Sushma et al. 2016), boosting cell resistance to chemotherapy. PTEN is targeted by miRNA-93 in breast cancer, resulting in increased treatment resistance of cells to CDDP. Furthermore, PTEN is targeted by miRNA-214 (Yang et al. 2008), miRNA486-5p (Zhu et al. 2019), miRNA-130a (Yang et al. 2012), miRNA-216a/217 (Xia et al. 2013), miRNA-92b (Li et al. 2013), and miRNA-205 (Lei et al. 2013).

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Thus miRNAs, such as miRNA-195, miRNA-503 (Qu et al. 2015), miRNA-1915 (Xu et al. 2013), miRNA-15a/16 (Cittelly et al. 2010), miRNA-181a (Li et al. 2013), miRNA-181b (Zhu et al. 2010), miRNA-200b (Zh), miRNA-106a (Rao et al. 2013), miRNA-193b (Mao et al. 2014), and miRNA-135a/b (Zhou et al. 2013), may also target Mcl-1 to enhance sensitivity to cis-diamminedichloroplatinum (II) (CDDP) and sorafenib in ovarian cancer, lung cancer, and hepatocellular carcinoma (HCC), respectively. Bak, a proapoptotic protein, could target and inhibit miRNA-125b increasing resistance to CDDP, doxorubicin (DOX), and paclitaxel (PTX) in APL, carcinoma of ovary, and breast cancer, respectively. PDCD4 is a potent tumor suppressor gene and induces apoptosis by inhibiting growth of the cell, tumor invasion, and metastasis. MiRNA-21, miRNA-106a, and miRNA-182 have been found to target PDCD4 and promote treatment resistance in pancreatic cancer, CML, non-small cell lung cancer (NSCLC), and ovarian cancer to gemcitabine (Wang et al. 2013a) and CDDP (Ning et al. 2014). P13K/AKT signaling pathway promotes cell proliferation and survival in many tumors. Many studies have revealed that miR-199a-3p can target mTAR and c-Met in HCC. Restoration of low levels of miR-199a-3p in HCC cells resulted in G (1) phase cell cycle arrest, reducing invasive capacity and increasing sensitivity to DOX-induced apoptosis (Fornari et al. 2010). P53 stops the cell cycle via inhibiting CDKs. Thus, p53 deficiency diminishes cell sensitivity to DNA damage that results in drug resistance. P53 may be suppressed by miRNA-125, rendering cells resistant to DOX (Kutanzi et al. 2011). The nuclear factor kappa-β (NF-Kβ) signaling pathway can induce a cascade of gene transcription factors that inhibits apoptotic process and enhances tumor cell resistance to chemotherapeutic agents. By inhibiting the NF-Kβ signaling pathway, the leucine-rich repeat interacting protein-1 (LRRFIP1), one of miRNA-21’s target genes, can reduce drug resistance. Thus, in the glioblastoma cell line U373MG, miRNA inhibition by particular antisense oligonucleotide increases the deleterious cytotoxic effects of teniposide (VM-26) (Li et al. 2014). Aberrant expression of TUBB3, for example, has been linked to ovarian as well as endometrial cancer resistance to microtubule inhibitors such as PTX and VCR. According to the literature, ectopic production of miRNA-200c downregulates TUBB3 and thereby increases the sensitivity to PTX, VCR, and epothilone B by up to 85% (Cochrane et al. 2009). Let-7 and miRNA-221/222 target ER-36 and ER, respectively, whereas TAM is an ER antagonist, to change breast cancer cell resistance to TAM (Zhao et al. 2011). Angiogenesis inhibitors such as bevacizumab target and block vascular endothelial growth factor A (VEGFA) and thereby enhance NSCLC sensitivity to bevacizumab (Zhu et al. 2012). These observations suggest that the combination of chemotherapeutic medicines and miRNAs may have a wide range of applications in the treatment of cancer. Drug-metabolizing enzymes function potentially in cancer treatment. The medication is converted into an active anticancerous form through metabolic reactions such as 5-FU. In addition, metabolic responses degrade the medication into inactive by-products. The cyt P450 (CYP) superfamily is known to be a drug-metabolizing enzyme group thought to catalyze the metabolism of important drug classes. With

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the increased expression of miRNA-148a in PXR, protein levels are reduced which results in CYP3A4 induction. Furthermore, miRNA-892a targets CYP1A1 and let-7b inhibits CYP212 (Choi et al. 2012). There is evidence that downregulation of CYP3A by miRNA-based shRNA results in decreased enzymatic activity considerably in transgenic mice (Wang et al. 2013b). The most predominant mechanism of the drug resistance is increased expression of drug efflux pump genes (Gottesman et al. 2002). These proteins have identical transmembrane domains and function by pumping the drug out of the membrane, thereby protecting tumor cells (Baguley 2010). Several recent investigations have discovered that miRNAs can target drug efflux pump genes directly and so influence drug resistance in cells. In HCC, for example, miRNA-223 targets ABCB1, reducing cell resistance to DOX (Yang et al. 2013). MiRNA-133a targeted ABCC1, increasing the cells’ susceptibility to ADM (Ma et al. 2015). MiRNA-298 binds ABCC1 in breast cancer cells, increasing cell sensitivity to DOX (Bao et al. 2012). ABCG2 inhibition in breast cancer MiRNA-328 and miRNA-487a has been shown to improve cell sensitivity to mitoxantrone (MX) (Pan et al. 2009). Other ABC-related genes, namely, ABCA1 and ABCB9, were affected by miRNA-31 and miRNA-106a. These genes regulate lung cancer cell treatment resistance to CDDP (Dong et al. 2014). Let-7c increased the sensitivity to gefitinib in NSCLC by targeting ABCC2 (Zhan et al. 2013). Some anticancer medicines, for instance, CDDP and DOX, cause cellular death by causing damage to DNA. The broken DNA strands need enzymes of DNA damage repair to fix damaged sequences. The cell survives when damaged DNA strands are repaired. Many enzymes are necessary for DNA damage repair, and expression changes can affect therapeutic resistance to substances which can damage DNA. Some miRNAs have the ability to reverse drug resistance, allowing them to target the genes related to DNA damage repair. In ovarian cancer, for instance, miRNA-9 targets BRCA1, enhancing cell susceptibility to CDDP (Sun et al. 2013). In NSCLC, miRNA-138 targets ERCC1 gene, enhancing sensitivity to CDDP (Wang et al. 2011).

1.4

Conclusion

We are in an advanced era of miRNA biology which is assuring promising therapeutic strategies. Around 2000 miRNAs are discovered to date in humans and are connected to the various cellular processes. Commercial efforts are quite rapid in bringing these diagnostic and therapeutic approaches from bench to bedside. However, there are certain limitations in miRNA research that has to be characterized. A complete understanding of their fundamental mechanisms can develop potential therapies and effective drug delivery methods.

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Fabbri M, Garzon R, Cimmino A et al (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 104(40):15805–15810 Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114 Fornari F, Milazzo M, Chieco P, Negrini M, Calin GA, Grazi GL et al (2010) MiR-199a-3p regulates mTOR and c-met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res 70(12):5184–5193 Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2(1):48–58 Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240 Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S et al (2005) A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 65(21):9628–9632 He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435(7043):828–833 Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293:834–838 Joshi D, Chandrakala S, Korgaonkar S, Ghosh K, Vundinti BR (2014) Down-regulation of miR-199b associated with imatinib drug resistance in 9q34.1 deleted BCR/ABL positive CML patients. Gene 542(2):109–112 Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256(1):42–49 Kuhnert F, Kuo CJ (2010) miR-17-92 angiogenesis micromanagement. Blood 115:4631–4633 Kutanzi KR, Yurchenko OV, Beland FA, Checkhun VF, Pogribny IP (2011) MicroRNA-mediated drug resistance in breast cancer. Clin Epigenetics 2(2):171–185 Lee RC, Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294(5543):862–864 Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854 Lei L, Huang Y, Gong W (2013) miR-205 promotes the growth, metastasis and chemoresistance of NSCLC cells by targeting PTEN. Oncol Rep 30(6):2897–2902 Lerner RG, Petritsch C (2014) A microRNA-operated switch of asymmetric-to-symmetric cancer stem cell divisions. Nat Cell Biol 16:212–214 Li Y, Li L, Guan Y, Liu XJ, Meng QY, Guo QS (2013) MiR-92b regulates the cell growth, cisplatin chemosensitivity of A549 non small cell lung cancer cell line and target PTEN. Biochem Biophys Res Commun 440(4):604–610 Li WQ, Yu HY, Li YM, Wang X, He J, Yan HZ et al (2014) Higher LRRFIP1 expression in glioblastoma multiforme is associated with better response to teniposide, a type II topoisomerase inhibitor. Biochem Biophys Res Commun 446(4):1261–1267 Liu X, Chu KM (2014) E-cadherin and gastric cancer: cause, consequence, and applications. Biomed Res Int 2014:637308 Lo AK, To KF, Lo KW, Lung RW, Hui JW, Liao G, Hayward SD (2007) Modulation of LMP1 protein expression by EBV-encoded microRNAs. Proc Natl Acad Sci U S A 104(41): 16164–16169 Loffler D, Brocke-Heidrich K, Pfeifer G et al (2007) Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood 110(4):1330–1333 Lu J, Getz G, Miska E, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838

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Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science 303:95–98 Ma J, Wang T, Guo R, Yang XY, Yin J, Yu J et al (2015) Involvement of miR-133a and miR-326 in ADM resistance of HepG2 through modulating expression of ABCC1. J Drug Target 23(6): 519–524 Mao K, Zhang J, He C, Xu K, Liu J, Sun J et al (2014) Restoration of miR-193b sensitizes hepatitis B virus-associated hepatocellular carcinoma to sorafenib. Cancer Lett 352(2):245–252 Melo SA, Kalluri R (2012) Angiogenesis is controlled by miR-27b associated with endothelial tip cells. Blood 119:2439–2440 Mott JL, Kobayashi S, Bronk SF, Gores GJ (2007) mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 26(42):6133–6140 Ning FL, Wang F, Li ML, Yu ZS, Hao YZ, Chen SS (2014) MicroRNA-182 modulates chemosensitivity of human non-small cell lung cancer to cisplatin by targeting PDCD4. Diagn Pathol 9:143 Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130(1):89–100 Pan YZ, Morris ME, Yu A-M (2009) MicroRNA-328 negatively regulates the expression of breast cancer resistance protein (BCRP/ABCG2) in human cancer cells. Mol Pharmacol 75:1374– 1379 Pasquier E, Andre N, Trahair T, Kavallaris M (2013) Reply: comment on ‘Beta-blockers increase response to chemotherapy via direct anti-tumour and anti-angiogenic mechanisms in neuroblastoma’-β-blockers are potent anti-angiogenic and chemo-sensitising agents, rather than cytotoxic drugs. Br J Cancer 109:2024–2025 Pfeffer S, Zavolan M, Grässer FA, Chien M, Russo JJ, Ju J, John B, Enright AJ, Marks D, Sander C, Tuschl T (2004) Identification of virus-encoded microRNAs. Science 304(5671):734–736 Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T (2007) MicroRNA expression profiling in prostate cancer. Cancer Res 67:6130–6135 Qu J, Zhao L, Zhang P, Wang J, Xu N, Mi W et al (2015) MicroRNA-195 chemosensitizes colon cancer cells to the chemotherapeutic drug doxorubicin by targeting the first binding site of BCL2L2 mRNA. J Cell Physiol 230(3):535–545 Rao YM, Shi HR, Ji M, Chen CH (2013) MiR-106a targets Mcl-1 to suppress cisplatin resistance of ovarian cancer A2780 cells. J Huazhong Univ Sci Technol Med Sci 33(4):567–572 Rinaldi A, Poretti G, Kwee I, Zucca E, Catapano CV, Tibiletti MG, Bertoni F (2007) Concomitant MYC and microRNA cluster miR-17-92 (C13orf25) amplification in human mantle cell lymphoma. Leuk Lymphoma 48:410–412 Salzman DW, Shubert-Coleman J, Furneaux H (2007) P68 RNA helicase unwinds the human let-7 microRNA precursor duplex and is required for let-7-directed silencing of gene expression. J Biol Chem 282:32773–32779 Samols MA, Skalsky RL, Maldonado AM, Riva A, Lopez MC, Baker HV, Renne R (2007) Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog 3:e65 Santhekadur PK, Das SK, Gredler R, Chen D, Srivastava J, Robertson C, Baldwin AS Jr, Fisher PB, Sarkar D (2012) Multifunction protein staphylococcal nuclease domain containing 1 (SND1) promotes tumor angiogenesis in human hepatocellular carcinoma through novel pathway that involves nuclear factor κB and miR-221. J Biol Chem 287:13952–13958 Sun X, Fan C, Hu LJ, Du N, Xu CW, Ren H (2012) Role of let-7 in maintaining characteristics of breast cancer stem cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 28:789–792 Sun CY, Li N, Yang ZY, Zhou B, He Y, Weng DH et al (2013) miR-9 regulation of BRCA1 and ovarian cancer sensitivity to cisplatin and PARP inhibition. J Natl Cancer Inst 105(22): 1750–1758 Sushma PS, Jamil K, Kumar PU et al (2016) PTEN and p16 genes as epigenetic biomarkers in oral squamous cell carcinoma (OSCC): a study on south Indian population. Tumor Biol 37:7625– 7632

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Thomson JM, Newman M, Parker JS et al (2006) Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 20(16):2202–2207 Wang Q, Zhong M, Liu W, Li J, Huang J, Zheng L (2011) Alterations of microRNAs in cisplatinresistant human non-small cell lung cancer cells (A549/DDP). Exp Lung Res 37(7):427–434 Wang P, Zhuang LP, Zhang J, Fan J, Luo JM, Chen H et al (2013a) The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol 7(3):334–345 Wang YY, Ren T, Cai YY, He XY (2013b) MicroRNA let-7a inhibits the proliferation and invasion of nonsmall cell lung cancer cell line 95D by regulating K-Ras and HMGA2 gene expression. Cancer Biother Radiopharm 28:131–137 Xia H, Ooi LL, Hui KM (2013) MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology 58(2):629–641 Xu K, Liang X, Cui D, Wu Y, Shi W, Liu J (2013) miR-1915 inhibits Bcl-2 to modulate multidrug resistance by increasing drug-sensitivity in human colorectal carcinoma cells. Mol Carcinog 52(1):70–78 Xue G, Yan HL, Zhang Y, Hao LQ, Zhu XT, Mei Q, Sun SH (2015) c-Myc-mediated repression of miR-15-16 in hypoxia is induced by increased HIF-2α and promotes tumor angiogenesis and metastasis by upregulating FGF2. Oncogene 34(11):1393–1406 Yang H, Kong W, He L, Zhao JJ, O’Donnell JD, Wang J et al (2008) MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 68(2):425–433 Yang L, Li N, Wang H, Jia X, Wang X, Luo J (2012) Altered microRNA expression in cisplatinresistant ovarian cancer cells and upregulation of miR-130a associated with MDR1/P-glycoprotein-mediated drug resistance. Oncol Rep 28(2):592–600 Yang T, Zheng ZM, Li XN, Li ZF, Wang Y, Geng YF et al (2013) MiR-223 modulates multidrug resistance via downregulation of ABCB1 in hepatocellular carcinoma cells. Exp Biol Med 238(9):1024–1032 Yu J, Wang F, Yang GH, Wang FL, Ma YN, Du ZW, Zhang JW (2006) Human microRNA clusters: genomic organization and expression profile in leukemia cell lines. Biochem Biophys Res Commun 349:59–68 Zhan M, Qu Q, Wang G, Zhou HH (2013) Let-7c sensitizes acquired cisplatin-resistant A549 cells by targeting ABCC2 and Bcl-XL. Pharmazie 68(12):955–961 Zhang J, Zhang H, Liu J, Tu X, Zang Y, Zhu J, Chen J, Dong L, Zhang J (2012) miR-30 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in hepatocyte by targeting Snail1. Biochem Biophys Res Commun 417:1100–1105 Zhao YC, Deng CS, Lu WD, Xiao J, Ma DJ, Guo MX et al (2011) Let-7 MicroRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor alpha signaling in breast cancer. Mol Med 17(11–12):1233–1241 Zhou L, Qiu T, Xu J, Wang T, Wang J, Zhou X et al (2013) miR-135a/b modulate cisplatin resistance of human lung cancer cell line by targeting MCL1. Pathol Oncol Res 19(4):677–683 Zhu W, Shan X, Wang T, Shu Y, Liu P (2010) miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines. Int J Cancer 127(11):2520–2529 Zhu X, Li H, Long L, Hui L, Chen H, Wang X et al (2012) miR-126 enhances the sensitivity of non-small cell lung cancer cells to anticancer agents by targeting vascular endothelial growth factor A. Acta Biochim Biophys Sin Shanghai 44(6):519–526 Zhu HH, Wang XT, Sun YH, He WK, Liang JB, Mo BH, Li L (2019) MicroRNA-486-5p targeting PTEN protects against coronary microembolization-induced cardiomyocyte apoptosis in rats by activating the PI3K/AKT pathway. Eur J Pharmacol 855:244–251

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MicroRNAs and Cancer Signaling Pathways K. Sri Manjari, Srilekha Avvari, Imran Ali Khan, and DKV Prasad

Abstract

Cancer is a condition where cells have gained the capability, generally due to genetic abnormalities in certain genes, of uncontrolled divisions and growth. This complex disease is dysregulated at many levels in different pathways. These pathways are closely linked with different stages of cancer. Cancer pathways comprises a series of actions between molecules in a cell that leads to a product or a change in a cell that can trigger the assembly of new molecules or turn genes on and off or spur a cell to change. Finding the genes, proteins, and other molecules involved in a pathway can offer clues on what goes wrong when a disease strikes. MiRNAs, the regulating molecules, are downregulated or upregulated in different cancers and pathways for the control and transition of cancer into various stages. MiRNAs are involved in transcriptional and translational repression as well as cleavage of mRNAs. This subtle involvement of miRNAs in cancer along with different pathways renders this disease challenging to comprehend. Understanding of the role of miRNA helps uncover novel therapeutic target to treat cancer by

K. S. Manjari (*) Department of Genetics and Biotechnology, University College for Women, Koti, Osmania University, Hyderabad, Telangana, India S. Avvari Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad, Telangana, India I. A. Khan Department of Clinical Laboratory of Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia D. Prasad Department of Biochemistry, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Prasad, P. Santosh Sushma (eds.), Role of MicroRNAs in Cancers, https://doi.org/10.1007/978-981-16-9186-7_2

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helping to know the causes of treatment failure. Identifying the molecular basis of cancer signifies a major breakthrough in the history of medicine, affecting the discipline from pattern recognition and beneficial approaches based on molecular mechanisms. The focus of this chapter is on exemplifying mechanistically how the miRNA pathway is involved, or affected by, cancer. Keywords

Cancer signaling · Transforming growth factor · SMAD · Kinase · Interferon · Growth factors · Cell cycle

2.1

Introduction

Cancer is a condition where cells have gained the capability, generally due to genetic abnormalities in certain genes, of uncontrolled divisions and growth (Hanahan and Weinberg 2000, 2011). Advances in DNA sequencing in the last decade have allowed these genetic changes to be thoroughly studied, and the common mechanisms and signals are well understood (Garraway and Lander 2013; Vogelstein and Kinzler 2004). DNA sequencing is turning out to be a part of clinical routine treatment as additional genetic modifications are targeted by specific medications (Hartmaier et al. 2017; Schram et al. 2017; Sholl et al. 2016; Zehir et al. 2017). There are, nonetheless, significant variations in genes and pathways among different tumor kinds and tumor samples, and a comprehensive understanding of all forms of cancer genes and pathways is important to uncover therapeutic possibilities and vulnerabilities (Fig. 2.1).

2.2

Regulation of the Transforming Growth Factor (TGFb1)/Sma Mothers Against Decapentaplegic (SMAD) Pathway

The TGFβ family, a cytokine family, has multifunctional capabilities and affects several cell functions such as cellular growth, differentiation, migration, adhesion, and death (Miyazawa et al. 2002). The signaling by TGFβ has several regulatory development roles. The pathogeneses are of different conditions, including various fibrotic diseases, cardiovascular disease, inflammation, and cancer, and have been connected with changes in this signaling pathway (Bierie and Moses 2006; Chen and Ten Dijke 2016; Meng et al. 2016; Pickup et al. 2013). Prior research showed that the miRNA route is an essential component of its downstream signal cascades through the TGFβ signaling path (Janakiraman et al. 2018). The function of TGFβ depends on the kind of tissue and epigenetic cell background (Roberts and Wakefield 2003). TGFβ biology is characterized by its dual functioning: in early stages, it works as a tumor suppressor while in advanced stages stimulates tumor cell metastasis. There has been extensive study of the relationship between TGFβ and

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Fig. 2.1 Cell signaling pathways

miRNAs, and studies show that the TGFβ route may either impede or improve miRNA maturation (Blahna and Hata 2012; Elston and Inman 2012). The pathway TGFβ1/SMAD contributes toward progression of cancer. The phosphorylated receptor-mediated Sma mothers against decapentaplegic (SMAD) signals trigger the buildup of active SMAD complexes within the nucleus which, in conjunction with transcriptional factors, histone modifiers, and chromatin remodeling devices, transcriptionally reregulate target genes (Ikushima and Miyazono 2010). In the intracellular transmission of the signals, the SMAD proteins play a vital role. SIRT7 affects SMAD4 decay by using β-TrCP1 as a repeat protein. The complicated assembly of the SMAD4, β-TrCP1, and SIRT7 results in the TGF path shutdown. Davis et al. (Davis et al. 2010) was the first person to report miRNA modulation and show that TGFβ therapy led to pre-miRNAs and mature miRNA upregulation, however not the treatment of pri-miRNAs. The transcription of miRNA-coding genes through interaction with miRNA promoter genes was found to influence SMAD proteins (Hata and Davis 2009). SMADs control miRNA biogenesis through two distinct ways which involve or do not bind complex Smad2–3 with Smad4. It is transported into the core where the Drosha/DGCR8 microprocessor complex is recruited and miRNA maturation is promoted (Blahna and Hata 2012; Hata and Davis 2009; Butz et al. 2012). The mechanism behind the translocation into the nucleus of Smad2–3, however, remains unknown. miR-181,

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miR-21, miR-10, and miR-494 are the most prevalent miRNAs increased by a TGFβ signal. Ligand binds to the development of heterotetramers through the TGFβ receptor (TβR). This signal is transmitted via the nucleus via the Smad (R-Smad). Activated complex R-Smads with common Smads (co-Smads such as Smad4) translocate and change miRNA transcription to the nucleus of the system. TGFβ signals can also be altered by non-Smad transcripts, including ERK, JNK/p38, PI3K/ Akt, and RhoA. It is common knowledge that most TGFβ pathologists are targeted by one or more miRNAs (Butz et al. 2012). TGFβRI, TGFβRII, and Smads dysregulated in the majority of malignancies following the identification of TGFβ1, although miRNAs that might potentially be targeted at these molecules are downregulated. MiRNA has thoroughly examined its impact on canonical Smad signaling.

2.2.1

TGFb1

Experimentally confirmed, interactions between miRNAs and TGFβ1 have shown that miRNAs regulate multiple-level TGFβ1 signaling. Some of these encounters were shown. For instance, Martin et al. (Martin et al. 2011) for miR-744 found several binding sites in the proximal TGFβ1 30 -UTR. Endogenous TGFβ1 hindered miR-744 transfection, which is potentially relevant because of the pleiotropic nature of TGFβ1 cell responses. Dogar et al. (2011) have demonstrated that lower levels of the TGFβ1-processing factors, thrombospondins1 (THBS1) and furin, representing the observed derepression of miR-18a and miR-24, indicated an innovative mechanism that would construct a regulatory feedback loop mediated by miRNA. Latent TGFβ1 ectopic expression reducing THBS1 protein expression is related with enhanced miR-18a and let-7 expression in cells (Dogar et al. 2014). These data show an inverse link between THBS1 and latent TGFβ1 levels with potentially miRNAs.

2.2.2

TGFbRI and TGFbRII

TGFβRI and Smad2 are upregulated by the downregulation of miR-200 or miR-30 in order to direct epithelial-mesenchymal transition (EMT) and aggressive anaplastic thyroid carcinomas. miR-128a aids letrozole resistance in breast cancer cells by targeting TGFβRI (Masri et al. 2010). To date, numerous miRNAs aimed at TGFβRII have been discovered and demonstrated to contribute to tumor growth in various malignancies. miR-590-5p enhances human hepatocellular carcinoma proliferation and invasion (Jiang et al. 2012), and miR-107b increases colorectal cancer cells migration and invasion (Feng et al. 2012). The increased nodal metastases and the advanced clinical stage compared to controls are connected with the high expression of miR-3700 in gastric cancer tissue, and miR-211 enhances the carcinogenesis of head and neck carcinomas (Chu et al. 2013). miR-21 also induces stemming by targeting TGFβRII in colon cancer cells and increases the formation

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of tumors in prostate cancer by targeting TGFβRII and Smad2/3 (Mishra et al. 2014). In triple negative breast cancer, the miR-520/373 family works as tumor suppressor by inhibiting TGFβRII. miR-655 dropped zinc finger E-box-binding homeobox 1 (ZEB1), and TGFβRII rises in order to speed up the development of cancer. Recently, cisplatin resistance was reversed and metastasized by targeting TGFβRII in NSCLC in the miR-17 family (Guo et al. 2016).

2.2.3

SMADs

The cancer-like cell characteristics of hepatocellular carcinoma cells in Smad are attenuated by the use of Smad miR-148a (Jiang et al. 2014a). miR-99a and miR-99b improve cell migration by targeting Smad3, as well as enhancing the adherence of normal mucous gland cells (Turcatel et al. 2012). miR-92b works by targeting Smad3 as a possible oncogene and encourages proliferation of glioblastoma cells (Wu et al. 2013a). miR-146b-5p enhances the spread of cells and the cell cycle stoppage of Smad4 by the repression of thyroid cancer (Geraldo et al. 2012). miR-9a functions by acting on Smad4 as a negative regulator of TGFβ signaling in gastric cancer (Zhang et al. 2012). miR-130a-mediated Smad4 decreases the susceptibility of granulocytic precursors of TGFβ1 activation (Häger et al. 2011). In addition, miR-130a/301a/ 454 is used to increase celled propagation and migration in human colorectal cancer as an oncogenic agent by targeting Smad4 (Liu et al. 2013). miR-34a is a tumor suppressor miRNA and targets Smad4 in a proneuronal glioblastoma subtype. Downregulated miR-146a promotes Smad4 and impacts cell proliferation in the cell line in response to retinal acid induction (Zhong et al. 2010). miR-155 resists growth inhibitory effects of TGFβ1 and BMP by targeted Smad5 to diffuse large B-cell lymphoma (DLBCL) cells. In addition, miR-155 modulates the retinoblastoma protein (RB) phosphorylation through the noncanonical signaling pathway TGFβ1/Smad5 in normal and malignant B lymphocytes. The miR-K12-11 herpesvirus-encoded sarcoma associated with Kaposi promotes cells proliferation by removing Smad5 (Liu et al. 2012). The miR-106b-25 group targets the Smad7 inhibitory protein, which is responsible for overexpression of TGFβRI and triggers TGFβ signaling to induce EMT and Six1, a therapy for tumors, in human breast cancer cells (Smith et al. 2012). In addition, miR-216a/217 stimulates EMT to promote the resistance to medicines and recurrence of liver cancer via targeting phosphatase and tensin homolog (PTEN) and Smad7 (Xia et al. 2013).

2.2.4

Other Mechanisms

The miR-106b-25/miR-17-92 hinders the arrest of the cell cycle and apoptosis to withstand TGFβ tumor removal (Petrocca et al. 2008). In addition, the cluster miR-106b-25 suppresses the pathway of TGFβ tumor support, which impairs the production of cyclin-dependent kinase inhibitor 1A (CDKN1A) and BCL2L11

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(Bim) in stomach cancer (Petrocca et al. 2008). The cluster miR-17-92 miRNA, which acts both upstream and downward, has shown that the TGFβ pathway is downregulated by several major influences and TGFβ-responsive genes can be inhibited into neuroblastoma cells (Mestdagh et al. 2010). miR-183 suppresses human hepatocellular carcinoma cell TGFβ1-induced apoptosis through the downregulation of pyruvate dehydrogenase complex deficiency (PDCD4) (Li et al. 2010). Moreover, miR-379 and miR-204 target the IL-11 and reduce the expression in bone-metastatic breast cancer cells of multiple genes that are implicated in TGFβ signaling, including PTGS2 (Pollari et al. 2012). miR-127-3p suppresses growth of cancer cells by targeting SKI proto-oncogenes (SKIs) in a glioblastoma and promotes TGFβ signaling (Jiang et al. 2014b).

2.2.4.1 Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway The pathways for MAPK are evolutionarily preserved to connect out-of-cell signal to their intracellular targets and to control basic cellular activities, including cell proliferation, cell growth, cell migratory processes, cell differentiation, embryogenesis, and cell mortality. Between 1989 and 1991, the first kinesis of the MAP was found in the budding yeast pathways (Saccharomyces cerevisiae), Kss1p, and mitogen-activated protein kinase (Fus3p) (Guo et al. 2020). 2.2.4.2 MAPK/ERK Protein MAPKs are eukaryotic protein SE/Thr kinases that are expressed by the MAPK1 gene and enabled by the MAPK signaling pathway upstream rapidly accelerated fibrosarcoma (RAF) (Cargnello and Roux 2011). The standard MAP kinases are assembled into three main families. These are extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38/SAPKs (stress activated protein kinases) (Morrison 2012). These include the ERKs. All of the MAPKs are composed of serine/threonine kinase, with different lengths flanked by N- and C-terminal domains. Some MAPKs include an alanine, histidine, or glutamine (alanine, histidine, and glutamine) domain (AHQr) (Cargnello and Roux 2011), the ERK3 and ERK4 (C34) area, as well as a nuclear localization sequence (NLS). It is well recognized that both RAS (rat sarcoma, the tumor where the first gene of the family was recognized) and RAF control are necessary for the adequate maintenance of cell proliferation, given the oncogenesis caused by activation of mutations in both genes (Karnoub and Weinberg 2008). Activated RAF binds to the double-specific kinases MEK1/2 and phosphorylates them, which in turn, in their active loop, are the phosphorylates ERK1/2 in the Thr-Glu-Tyr (TEY) motif (Roberts and Der 2007). In MAPK1 expression, many miRNAs, miR-17 and miR-19a, are regulated directly by MAPK1. miR-17 and miR-19a belong, respectively, to miR-17 and miR-19 and are members of the highly preserved vertebrate miR-17-92 cluster (Mogilyansky and Rigoutsos 2013). These two miRNAs are found on chromosome 13 of men (13q31.3). A major chronic myeloid leukemia (CML)-associated oncogene is the 17–92 miRNA cluster. A survey showed that the overexpression of this cluster in cell line K562 increases cell proliferation (Wang et al. 2008).

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RAS-MAPK pathway activation is one of the most common oncogenic occurrences in human cancer. Oncogenic RAS mutations take place in around 30% of the tumor, although mutations are also highly widespread in numerous tumor types in upstream and downstream regulators. Independently of the etiology, a cancer-related RAS signal is often optimizable by amplifying mutant RAS genes or eliminating negative feedback mechanisms. This emergence element of tumor development is thought to be supported by epigenetics. Most miRNAs were reported as stimulating the RAS-MAPK pathway in many forms of cancer and acting as an oncogenic RAS rheostat, which increases as tumors move forward. There is far from comprehensive clarification of specific processes leading to dysregulation of miRNAs and of the functional implications in cancer. As one miRNA can influence the same transcript by thousands of genes and hundreds of miRNAs, it is extremely tough to effectively predict miRNA aims. Computer tool reliability is not fully valid. It is extremely tough to integrate the several distinct miRNAs with the RAS-MAPK pathway objectives for human malignancies. Bioinformatic data integration tools (miRNAome) are necessary, as well as interpretation and depiction of the different miRNA expressions. In addition, miRNA expression distinctions in cancer should be understood carefully, since correlations may differ from causal variables. The cellular milieu should be considered, and miRNA dysregulation in vitro or in vivo models should be proven experimentally. Here we give a large map of miRNAs that have been demonstrated to target RAS-MAPK molecules experimentally. Dysregulation of miRNAs targeting the RAS-MAPK pathway may be a continuous carcinogenic event. As oncogenes (oncomiRs) or suppressing tumor, miRNAs may act. OncomiRs are designed to eliminate tumor suppressor expression in genes (Bos 1989). In contrast, oncogene expression, such as KRAS, was repressed by tumor-representative miRNAs like let-7 and miR-34. Active MAPK caused miR-7 to be upregulated, while miR-181d, miR-34a, and miR-193b were downregulated. One such miRNA causes the exogenous overexpression of cultivated pancreatic cancer cells to proliferate. miR-193b had the most inhibitory effect. MAPK activity was reduced by the promoters of host genes of miR-7-3 and miR-34a. In addition, we found the CCND1, PLAU, NT5E, STARD7, YWHAZ, and STMN 1 target genes of miR-193b.

2.2.5

Signal Transducer and Activator of Transcription 3 (STAT)-Related Signaling Pathway in Cancer

STATs belong to an interferon (IFN) response family of transcription factors. The seven STAT3s are a key part of the family of STAT proteins which is activated during inflammation and cancer (including STAT1, STAT2, STAT3, STAT4, STAT5-a, STAT5-b, and STAT6) (Rawlings et al. 2004). STAT3 is activated by cytoplasmic to nuclear shuttle and phosphorylation. An earlier work showed that STAT3 tyrosine phosphorylation contributes to Src oncogenesis. Following research by cells and animals verified that activation by STAT3 is a mediator of malignant tumor transformation. The upstream component of Janus kinase (JAK) modulates

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STAT biological activity 3. Interleukin 6 (IL6), which has biological effects for malignancies, is an inflammatory cytokine which is also associated with the IL6 receiver (IL6R). JAK family members are phosphorylated with gp130 following the IL6/IL6R complex. The JAK/STAT signaling pathway, which is operating by combining with JAK catalytic sites, is the main negative regulatory body for the SOCS family (CIS, SOCS 1–7). The activated STAT3 protein inhibitor (PIAS 3) reduces STAT3’s DNA-binding activity and so hinders STAT3 activation, showing PIAS3 is a particular STAT3 inhibitor (Chung et al. 1997). MiRs attempt to suppress the phosphorylation of JAKs among members of the JAK family, which in turn reduces the production of STAT3 as a tumor suppressor. By targeting directly JAK1 as a tumor suppressor in HCC, miR-340 prevents cell proliferation and invasion. By targeting JAK2 in breast, pancreatic, stomach, and bladder cancer, miR-204, miR-216a, and miR-375 inhibit the JAK2/STAT3 signal pathway. miR-125b and let-7c limit cholangiocarcinoma (CCA) migration in the form of IL6R targets, invasions, proliferation, and apoptosis. In cervical cancer, miR-9 aims at IL6 indirectly to decrease STAT3. On the other hand, when miRs target suppressor of cytokine signaling 3 (SOCS) proteins, which activates STAT3, the JAK/STAT report is active (Zhang et al. 2016). STAT3 may be upgraded by miR-156-5p, miR-19a, miR-30, and miR-155 by targeting SOCS1, oral squamous (OSCC), non-small cell lung carcinoma (NSCLC), and prostate and pancreatic cancer. Tests may be targeted against the disease. By targeting SOCS2 at prostate cancer, miR-194 works as an oncogene. STAT3 is activated by targeting SOCS3 in various malignancies miR-222-3p, miR-221, miR-4308, miR-322-3p, miR-203, and miR-30. The aim is miR-18a for suppressing STAT3 in gastric adenocarcinoma, as protein inhibitor in active STAT3. In short, miRs regulate the STAT3 by targeting its traditional signaling path to prevent or enhance the production of STAT3-interacting proteins that show a complex system of interactions in the regulatory mechanism (Zhang et al. 2017).

2.2.6

PI3K Signaling, miRNA, and Cancer

Phosphoinositide 3-kinase (PI3K) is a family of three-group enzymes initially found out in 1985 (Kaplan et al. 1987). Class-I PI3Ks are best defined and involved in cancer because of their role in cell differentiation, metabolism, inflammation, motility, and progression in cells (Whitman et al. 1985). PI3Ks can be triggered through several membrane receptors such as PDGFR (platelet-derived growing factor receptor), EGFR (epidermal growth factor receptor), and a variety of stimulus including growth factors, cytokines, and hormones (Vanhaesebroeck et al. 2010). AKT (also named kinase B or PKB) is activated by downstream of PI3K. One of the most often stimulated signal transduction pathways in cancer is characterized as a PI3K/AKT signaling pathway (Whitman et al. 1985). MiRNAs can have a direct effect on gene expression by attaching the target mRNA to the 3 untranslated region (UTR) triggering destruction or repression of transcript mRNAs in the target gene. There are findings that miRNAs can affect the genes

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that are central to the pathway of PI3K/Akt signaling through these pathways. miR-133a, miR-21, let-7, miR-205, miR-130b, miR-200, miR-106b, and miR-155 were among the miRNAs reported to alter that route (Martini et al. 2014). One of the largest ways of combining dysregulated miRNA levels in Josse et al.’s study and his fellow workers was the PI3K/Akt signaling route (Welch et al. 2002). miR-143, miR-133a, miR-145, and miR-223 were identified as crucial to that signal pathway. We have found miR-145-5p to only be insulin-like growth factor 1 (IGF-1), BRCA1 (breast cancer), platelet-derived growth factor receptor alpha (PDGFRA), cholinergic receptor muscarinic (CHRM2), thrombospondin 1 (THBS1), and tenascin XB (TNXB) related. Other miRNAs formerly related with the PI3K pathway genes include the following: miR-590-5p, miR-106b, and miR-93 with PTEN; miR-497 with IGF1R; miR-451 with liver kinase B1 (LKB1), PI3K, AKT, and BCL2 (Gewinner et al. 2009). The links with various genes along the route between miR-497 and miR-106b-5p, with an emphasis on these genes with higher FCs, result in discrepancies in the detection of correlations between the study and the literature. As a result, miRNAs were not used to evaluate the genes with lower FC, such as PTEN and AKT.

2.2.7

Kirsten Rat Sarcoma Virus (KRAS) Signaling Pathway

In more than 90% of individuals with pancreatic duct adenocarcinoma (PDAC), KRAS mutations are observed in colorectal cancer, lung adenocarcinomas, and urogenital malignancies (Kanda et al. 2012; Timar and Kashofer 2020). Many miRs have been identified as important regulators of the KRAS signaling pathway for PDAC throughout the past few years. In particular, miR-217 works as a PDAC tumor suppressor that targets oncogene KRAS directly. miR-217 causes the AKT downstream signal transducer to lower its constitutive phosphorylation (Zhao et al. 2010). A study carried out by Yu et al. further shows that miR-96 does not just target KRAS but also modifies negatively the phosphorylated AKT pathway downstream of KRAS (Yu et al. 2010). Additional investigations have shown that miR-126 and let-7d target KRAS through posttranscriptional upregulation (Jiao et al. 2012). In PDAC cells, an active KRAS (G12D), which was connected to a poor prognosis in PDAC, can also boost the miR-21 promoter. The tumor suppressor in PDAC is miR-206 and both oncogenes of KRAS and annexin (ANXA2) were found to be inhibited (Vorvis et al. 2016). As a result, miR-206 may be a negative regulator of oncogenic NF-kB transcriptional activity induced in KRAS, leading to a reduction in proangiogenic and proinflammatory factors leading to additional tumor growth and low forecasting (Keklikoglou et al. 2015). The overexpression in PDAC was discovered to be miR-27a associated with lowering cell proliferation and migration. In particular, Sprouty2, which controls the KRAS expression, has a miR-27a direct target (Ma et al. 2010). An active KRAS, which increases proliferation of PDAC cells, is used to suppress overexpression of miR-143/145. The activated KRAS can also be used to trigger downstream repositories such as MAP2K1/MEK and MAPK1/ERK2. The MAPK signaling pathway has been proven by Collisson

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et al. (Collisson et al. 2012) that it is involved in the generation of PanIN, particularly at the early stages of development of the PDAC. MiRNAs operate as negative modulators of RAS but include also downstream miRNA effectors in the interplay between miRNAs and RAS. Non-small cell lung cancer (Ferro and Falasca 2014) and the squamous cell carcinoma of the laryngeals and the pancreatic adenocarcinoma (Sarkar et al. 2013) as well as a large number of other human cancers are unquestionably the most prominent miR-21 mutants that are upregulated by KRAS. miR-21 is a known oncomiR capable of suppressing the expression of PI3K-AKT pathway tumor suppressor genes like PTEN or RAS-MAPK pathway like PDCD4 or RASA1 (Mortoglou et al. 2021).

2.2.8

Cell Cycle Signaling Pathway

Cyclin D synthesis and CDK4/CDK6 activation are the first reaction to stimulation of the growth factor (Ladha et al. 1998; Ohtsubo and Chibazakura 1996). Cyclin D-CDK4/6 is then used to bind and inhibit E2F, Rb, a renowned tumor suppressor (Knudsen and Knudsen 2008). This releases the E2F and transcribes genes whose product is necessary for progression of the cell cycle and replication of DNA. Cyclin D1 overexpression and p16 inactivation are extremely prevalent events in pancreatic cancer that emphasize the relevance of G1 disease development disruption (Chen et al. 2009a, b; Fry et al. 2008). Inactivation of numerous cell cycle regulatory mechanisms may lead to pancreatic cancer aggressiveness. Large studies show that miRNAs perform important functions in the genesis and progression of pancreatic cancer. Zhao and his colleagues (2013) found that miR-192 encourages cell growth in the G1 to the S stage in pancreatic cell lines and aids cell cycle progression. In the in vitro colony formation test and in a xenograft tumor model in vivo, the growth-promoting effects of miR-192-forced expression were demonstrated. Of interesting note, the expression of cell-cycle positive regulators like cyclin D1, cyclin D2, CDK4, CDC2, and SKP2 was reduced after miR-192 overexpression. Another study found that miR-301a encourages the proliferation, at least partially, of pancreatic cancer cells by targeting Bim gene 30 UTR directly (Chen et al. 2012). Bim acts as an apoptotic stimulus sensor and starts apoptosis by activating proapoptotic protein such as BCL2-associated X, apoptosis regulator (Bak and Bax) in several areas (Willis et al. 2005). ERK pathway activation is known for the prevention from apoptosis and to regulate the growth of the pancreas tumor cells throughout the cell cycle (Boucher et al. 2000). miR-424-5p in pancreatic cancer specimens was discovered to be often elevated to influence the ERK1/2 signaling system via adjusting SOCS6 adversely. Further data supporting this opinion shows that miR-424-5p downregulation impedes the expression of the downstream SOCS 6 targets, namely, Bcl-2 and MCL2, and hence diminishes ERK trajectory activity (Wu et al. 2013b). A recent study revealed a participation in pancreatic cancer in the dysregulation of the KRAS axis by miR-193b. In particular, miR-193b functioned as a cell cycle brake in PDAC cells through G1 induction and reduction of cell fraction in the S phase resulting to

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decreased cell growth. Also, miR-193b was controlled by anchorage-independent growth suppression by malignant transformation phenotype of PDAC cells. Mechanistically, KRAS has been checked as a direct miR-193b effector, modulating the AKT and ERK pathways and suppressing the cell development of PDAC cells (Vorvis et al. 2016; Jin et al. 2015).

2.2.9

Notch and Hedgehog Signaling Pathways

A poor PDAC prognosis was associated with the Notch signalizing pathways, essential to tissue proliferation, organ development, and cell differentiation and death (Gironella et al. 2007; Radtke and Raj 2003). Notch homolog 1 (Notch) activation has the carcinogenic role of contributing to the autonomy of the stem cell, proliferation, migration, apoptosis, invasion, angiogenesis, and metastasis (De La and Murtaugh 2009). The blockage of the Notch signaling track is linked to NF-SB activity mitigation and p21-p27 upregulation (Wang et al. 2006). Early PanIN lesions are showing increased expression of the Notch pathway genes (Miyamoto et al. 2003). Several miRs in PDAC have been shown to be linked to the Notch pathway. Specifically, TP53 can directly control miR-34, leading to downstream Notch objectives (Vorvis et al. 2016). The following are also possible. In addition, Notch-1/2 can be decommitted in PDAC cancer stem cells (CSCs) (Ji et al. 2009) via the restoration of miR-34 expression. In addition, chromatinmodulating drug treatment of PDAC stem cells may also lead to the removal of miR-34 targets, such as Bcl-2, CDK6, and SIRT1 (sirtuin). Brabletz and his colleagues have also studied how miR-200 can block Notch pathway components such as Jagged1 and Maml2 and Maml3 mastermind-like coactivators which further increase the activation of Notch via EMT and ZEB1. Additional findings show that the upregulation of miR-145 and the downregulation of let-7a and miR-200 not only produce a reduction in expression of transcription factors associated with EMT but also Notch-1 inhibition through miR-144 (Sureban et al. 2013). As an embryonic development regulatory body, the Hedgehog signaling pathway (HH) also works as a moderator for cancer stem cells (i Altaba et al. 2002). In particular, PDAC has noticed multiple cases with deregulations in HH. Previous studies reveal that PanIN lesions upregulate the activity of such pathway and that PDAC development can be controlled by HH at early and late stages (Thayer et al. 2003). In cell cycle progression and apoptosis in PDAC, the HH pathway also plays a significant role. Therefore, an innovating therapeutic approach for the PDAC could be the inhibition of multiple HH pathway components (McCleary-Wheeler et al. 2012). Dosch et al. (2010) investigation showed that the secreted ligand, Hedgehog, can bind to the Patched1 receiver (PTCA1). In PDAC, miR-212, which is overexpressed in this malignancy, can downregulate PTCA1. The effect on cell proliferation, migration, and invasion via the HH route might be negative (Ma et al. 2014). For the discovery of new drugs and design of novel therapeutic techniques for pancreatic cancer, the molecular knowledge of Notch signals pathway. Notch signals have been shown to influence the self-renewal and differentiation of the stem cells

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and to play a role in pancreas carcinogenesis. In the onset of pancreatic carcinogenesis, it has been envisaged that the activation of Notch and KRAS shows synergistic effects (De La and Murtaugh 2009). Of interest, simultaneous inhibition of EGF and Notch pathways leads, with associated rise in cell death, to a decrease in cell growth. Blocked Notch cascade signaling also demonstrated that the activity of the NF-ŚB was diminished and p21 and p27 upregulated (Wang et al. 2006). Many miRNAs are revealed to collide with the Notch route in human PDAC. Preclinical investigations have demonstrated that TP53 regulates miR-34 directly, which also affects Notch downstream, demonstrating the role of the initiating cells of PDACs in their maintenance and survival. Clearly, treating chromatin-modulating agent (CSCs) for pancreatic cancer stem cells has led to the inhibition of Bcl-2, CDK6, and SIRT1 as the possible targets of miR-34a (Nalls et al. 2011). In addition, restoration of miR-34 expression in pancreatic CSCs downregulates Notch-1 and Notch-2, with high Notch-1 and Notch-2 in tumor initiating cells, similar with miR-34 expression losses. These data suggest that self-renovation of starting cells for pancreatic tumors is related to Notch’s direct control by miR-34 (Ji et al. 2009). As Brabletz and colleagues (2011) illustrate, miR-200 members aim for components of Notch pathway, such as Jagged1 and the Maml2 and Maml3 mastermind coactivators, thus enhancing Notch’s activation by ZEB1 and EMT activator. These results form a link to Notch activation for the latter and its cancer-fostering properties. In addition to the analysis, a miR-145 increase, let-7a and miR-200 were discovered, resulting in a considerable reduced pluripotency of the xenografts without the expression of the pancreatic stem cell marker DCLK1 and an inhibition of Notch-1 by miR-144 (Brabletz et al. 2011).

2.2.10 APC Signaling Pathway Progressive colorectal cancer (CRC), including adenomatous polyposis coli (APC), accompanies an accumulation of mutations in tumor suppressor genes and oncogenes (Pandurangan 2013). Colorectal carcinogenesis inactivation of APC is one of the primary initiatory events (Miyaki et al. 1994). In particular, the primary cause of CRC is mutations in APC (Powell et al. 1992). In all individuals with family adenomatous polyposis and in over 90% of patients with a CRC diagnosis, mutation in APC was detected (Coppedè et al. 2014). Most APC mutations have premature stop codons that produce shortened proteins that are not binding to β-catenin. The extracellular Wnt proteins stimulate the Wnt signal pathway through APC-free β-catenin, hence enabling active transcription of the target gene such cyclin D1 and c-Myc (Morin et al. 1997; Munemitsu et al. 1996). miR-494 is one of the largest miRNA clusters in the human genome in the Dlk1-Dio3 region that lies on the chromosome 14q32 of humans. The miR-494 expression patterns are not consistent among various tumor types, indicating, among other potential mechanisms, tissuedependent expression control of the miRNA (Zhang et al. 2018). The data strongly imply that overexpression of miR-494 is in harmony with the course of clinical CRC and miR-494 can work as an onco-miRNA.

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Wnt activation starts with the Wnt protein attaching to the frizzled class receptor 1 (FZD) and LDL receptor-related protein (LRP5 or LRP6), which are well known. The route is suppressed if miRs target Wnt ligand/receptor such as wingless-related integration site (WNT), FZD, and LRP. It was revealed that both miR-122 and miR-148a are downregulated in HCC and the Wnt route was repressed with WNT1. The growth of cells and the promotion of apoptosis was suppressed by miR-122 (Valencia-Sanchez et al. 2006). The use of EMT and cancer stem cell such as characteristics was reported to limit HCC metastasis (Miranda et al. 2006). miR-148a the Wnt ligand is also a target to suppress Wnt/β-catenin signaling path, as well as miR-22, miR-185-3p, miR-200b, miR-324-3p, miR-487b, miR-26a, miR-410, miR-329, and miR-374b. The tumor suppressors are another set of miRs targeting FZD and LRP. The Wnt pathway was, for example, inhibited by FZD7 and FZD8 to reduce breast cancer development, as miR-1 and miR-100 were discovered. The glioblastoma cell proliferation of miR-513c was mostly repressed by direct inhibition of LRP6 expression (Edwards et al. 2008; Sun et al. 2014; Wang et al. 2007).

2.2.11 Hippo Signaling Pathway in Cancer The Hippo mammalian pathway is comprised of 19 key genes. Core kinases cascade in Hippo mammalian signaling system and are composed of LATS1/2, MST1/2, and WW45 proteins, including MOB kinase activator 1 A/B (MOB1A/B). They are activated by TAOK (TAO kinase 1) phosphorylation and, by activation, phosphorylate the transcription coactivators YAP (yes-associated protein 1) and TAZ (tafazzin), keeping them in the cytoplasm (Boggiano et al. 2011; Poon et al. 2011). These are activated by phosphorylation. DROSHA and DGCR8 (DiGeorge syndrome critical region 8) together with other cofactors such as hNRNP A1 (heterogeneous nuclear ribonucleoproteins), p68 and p72, SMAD, and BRCA1 are the primary elements of the microprocessor. YAP has been demonstrated to control cell-dependent miRNA biosynthesis. At low cell density, nuclear YAP binds to p72, but Hippo-mediated phosphorylation and cytoplasmic YAP retention at high cell density enable p72 to be associated with microprocessor. It was hypothesized that Hippo pathway or the constitutively active YAP should be inactivated, and so the Hippo pathway links the contact-inhibition regulation with miRNA biological genesis (Mori et al. 2014). In the case of Dicermediated pre-miRNA, depending on the Lin-28 homolog A (LIN28/let-7 axis), the nuclear TAZ/YAP was demonstrated to facilitate further linkage between the contact inhibition and miRNA production by the Hippo pathway (Chaulk et al. 2014). Overexpression of miR-9 has been shown to encourage metastasis by downregulating the LIF receptor subunit alpha (LIFR), an upstream Hippo signal and LIFR restorer in malignant cells, which has suppressed the metastasis, by changing scribe location and enhancing MST1/2 and large tumor suppressor kinase 1 (LATS1) phosphorylation cascade (Chen et al. 2012). Overexpression of miR-9 and LIFR protein, followed by the sequestration of the TAZ shows that miR-125a

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controls the CSC population via Hippo signaling (Nandy et al. 2015) reduced the stem cell population in MCF7 cells. In breast cancer specimens, miRNA-135b has a high level of overexpression in BC cell leading to cell proliferation, migration, invasion, and cell cycle disruption as the miR-135b has been directly bound to LATS2’s 30 UTR (Hua et al. 2016). In the ccRCC cells, miR-10b has been shown to be downregulated, while YAP1 and homeobox (HOXA3), repressed by ccRCC proliferation, migration, and invasion, have been silenced. The miR-10b has been shown to play a function in tumor suppressors by targeting its direct HOJA3 target, which partially crosses the signaling pathway of FAK/YAP (He et al. 2019). In addition, the suppression of miR-21, through upregulation of LATS1 expression in Caki-2, has been proven to lower the expression of tumor stem cell markers and suppressed cell propagation. A study further shows that the expression of miR-572 in tissues and cell lines of RCC has been elevated and miR-572 suppression in 786-O cells has resulted in lower proliferation and enhanced apoptosis by controlling its direct NF2 expression (An et al. 2017).

2.2.12 p53 Pathway Recent investigations have shown that p53 speaks multilevel with miRNAs. First, p53 stimulates a series of miRNAs, including miR-34a/b/c, miR-107, miR-145, miR-215, and miR-192, to be transcribed. The involvement of p53 in tumor suppression has been found to be mediated through apoptosis, cell cycle arrest, and/or senescence. Second, p53 encourages the Drosha-mediated treatment and maturation of some miRNAs, notably miR-16-1, miR-143, and miR-145. Simultaneously, p53 monitors miRNA ripening, and the lack of miRNA ripening activates p53 and leads to p53-mediated senescence. Third, miRNAs may regulate the function p53 negatively through the direct repression of the p53 protein, or by the control of some negative regulators of the p53 protein, they can positively regulate p53 activity and function. For example, p53 can be regulated negatively by certain miRNAs like miR-504 or miR-125b, which can directly regulate the level and function of p53 proteins. At the same time, some individual miRNAs are favorably regulated by the p85α (by miR-29), SIRT1 (by miR-34a), or cyclin G1 suppression (by miR-122). These results have shown that miRNAs can be a new category of p53 target genes to influence the p53 function in tumor suppression by regulating the transcription expression and/or maturation of certain miRNAs by p53. Simultaneous miRNAs could be a new regulatory group for p53 that would unite kinase panels (e.g., ATM, ATR), all-armed ligases (e.g., mouse double minute 2 homolog (MDM2), Cop1, Pirh2), and phosphatases (e.g., Wip1, PP2A), such that p53 levels and activity could be closely regulated (Feng et al. 2011). Emergent data have shown that miRNAs may act in carcinogenesis as oncogenes or as tumor suppressor genes. For example, in many malignancies, including lymphoma and colorectal cancer, the miR-17-92 cluster miRNAs, which are translated as a polycistronic unit, are very expressed. The oncogenic effect of c-Myc can

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be increased and can therefore work as an oncogenic (Diosdado et al. 2009; He et al. 2005; Mu et al. 2009). In lung and liver tumors, miR-221 and miR-222 are often overexpressed. Overexpression of PTEN and TIMP metallopeptidase inhibitor 3 (TIMP3) tumor suppressors has been shown to increase tumor originality by downregulation (Garofalo et al. 2009). Some miRNAs were revealed to be tumor suppressors, on the other hand. Let-7 miRNAs can remove the expression of oncogenes, including Ras and c-Myc, directly and consequently have tumorsuppressive activities (Johnson et al. 2005; Roush and Slack 2008). Their expressions are often degraded in several malignancies, including lung and colorectal tumors, consistent with their activities in tumor suppression (Johnson et al. 2005; Roush and Slack 2008). In about 65% B-cell chronic lymphocytic leukemia, miR-15a and miR-16-1 are deleted or decreased (B-CLL). The anti-apoptotic protein BCL2 may be adversely regulated. The decreased expression of miR-15a and miR-16-1 thereby increases BCL2 and lowers apoptosis, contributing to malignant change (Calin et al. 2008). It has been recently discovered that p53 enhances the Drosha-mediated treatment of several miRNAs in cells in response to DNA damage, like doxorubicin treatments, using growth-suppressive capabilities including miR-16-1, miR-143, and miR-145. These miRNAs are lowered in different human malignancies, and their overexpression reduced the growth of tumor cells. These miRNAs negate certain essential cell cycle and cell proliferation regulators such as KRAS (as a miR-143) and CDK6 (as a target of miR-16-1 and miR-145). The study has also shown that in doxorubicin-treated cells p53 interacts with Drosha and p68 and p72 are essential for this interaction. In response to doxorubicin, p53 also mediates the interaction of pri-miRNAs with Drosha, and it is necessary for the enhanced Drosharelated pri-miRNA treatment. In addition, DNA mutations in the p53 gene, such as R175H and R273H prevalent in tumors, may lead to lower processing of pri-miRNAs by drosha and lower pri-miRNA levels, including miR-16-1, miR-143, and miR-145 in cells. These conclusions show that a tumor-suppressive scheme under p53, which could be a new mechanism by which p53 mutation can contribute to cancer, is fundamentally integrated into the transcription-independent control of miRNA biogenicity. Further research would identify the whole range of miRNAs whose maturation is regulated by p53 via the aforesaid mechanism and would further clarify the specificity of the recognition of pri-miRNAs (Suzuki et al. 2009). Although p53 encourages miRNAs to mature, p53 monitors miRNAs as to their ripening. Loss of miRNA maturation can trigger the signaling p53 and cause the medium senescence p53 (Mudhasani et al. 2008). Dicer ablation and loss of mature miRNAs in embryonic fibroblasts activate p53, which may be saved if p53 is deleted (Mudhasani et al. 2008). As p53-mediated senescence is a crucial functioning mechanism in the control of tumor, p53 loss of function can considerably enhance the tumorigenic potential of cells with lower ripe miRNAs. p53 induces a series of miRNAs, including miR-34a/b/c, miR-145, miR-107, miR-192, and miR-215, that can all contribute to the tumor suppression role of p53 as a new set of target p53 genes. miR-34a/b/c stimulates the downregulation of

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CDK4 and CDK6 to enhance apoptosis in cell cycle arrest and also BCL2 downregulation. miR-145 decommits c-Myc for cell proliferation to be reduced. miR-192 and miR-215 regulate genes to trigger the cell cycle arrest and tumor cells to limit growth and DNA synthetics, such as CDC7, mitotic arrest deficient 2-like protein 1 (MAD2L1), and Cullin 5 (CUL5); miR-107 decompresses beta of hypoxiainducible factor 1-alpha (HIF-1) to adjust hypoxia and to stop angiogenesis (Georges et al. 2008). p53-dependent MYC apoptotic mechanisms are well established. p19Arf activation by MYC is commonly included (Zindy et al. 1998). Arf then counteracts Mdm2, a ligase E3 ubiquitin which normally aims at p53 to degrade proteasomes (Haupt et al. 1993). Moreover, tp53, as well as expression, and phosphorylation of Mdm2 are known to directly be activated by MYC. By contrast, MYC’s mechanics are not well understood for p53-independent apoptosis. In other circumstances, p53-independent p19Arf effects could be incorporated (Boone et al. 2011; Qi et al. 2004). But, especially in B-cell lymphomas, the Ink4a locus, which encodes Arf, is often deleted. Noxa and Bim, a well-known direct MYC target, are also major mediators on MYC-driven p53-dependent apoptosis (Hemann et al. 2005). Nuclear factor erythroid factor 2 (NRF2) is the primary transcription factor that moves in the cells of the reactive oxygen species (ROS) cellular damage antioxidant reactive (ARE)-antioxidant gene network. The first miRNAs that had a positive stimulation on NRF2 transcription were 7b and 7c that certainly control expression of the human hepatoma Huh-7 and liver cell transcription factor, BTB, and CNC homology1 (BACH1). This resulted in an increase in NRF2-mediated expression of HO-1 and an attenuation of the oxidative stress mechanism (Hou et al. 2012; Reichard et al. 2007). A decrease in the level of miR-19b in the acetaminophen (APAP) treatment have been seen in LO2 liver cells. In turn, it results in sirtuin-1 (SIRT1) encouragement that boosts and enhances the hepatotoxicity of the NRF2 cascade with its linked downstream target genes (Liu et al. 2019). miR-32 helps to activate 3-kinase phosphoinositide (PI3K), which in turn upregulated NRFR2, in prostate cancer. Through the promotion of survival in cultivated human epithelial retinal pigment (RPE) cells, NRF2 thus generates a positive feedback loop (Wang et al. 2008). The overexpression of the peroxiredoxin-like 2A (PRXL2A) gene has been found to be activated in the oral squamous cell carcinoma (OSCC), which is subsequently suppressed by the overexpressing oxidative stress of positive feedback loops that have been involved in the pathway of NRF2 signaling (Chen et al. 2019). Transfection tests with a miR-144 mimic were found in the neuroblastoma SH-SY5Y cells to accelerate death, reducing the expression of numerous glutathione (GSH) production NRF2-controlled enzymes and reactive oxygen-scavenging species (Zhao et al. 2010). The link between miR-153-3p and NRF2 was found in lines of breast cancer cells, where low levels of miR-153-3p expression linked with an increase of NRF2 levels and downstream levels in the gene with a subsequent tumor cell migration/invasion stimulation (Wang et al. 2016). The finding that miRNAs can circulate between diverse cell types and cause biological effects, supporting or inhibiting the growth or distribution of tumors, has changed our thinking on tumor start and metastatic pyramidal cascades. In our

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current knowledge, we are certain that intercellular communication through miRNA will increasingly be identified as a fundamental biological mechanism that medicines for the treatment of cancer and many other disorders can affect (Berindan-Neagoe and Calin 2014).

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Zhao W-G, Yu S-N, Lu Z-H, Ma Y-H, Gu Y-M, Chen J (2010) The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS. Carcinogenesis 31(10):1726–1733 Zhao C, Zhang J, Zhang S, Yu D, Chen Y, Liu Q, Shi M, Ni C, Zhu M (2013) Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma. Oncol Rep 30(1):276–284 Zhong H, Wang H-R, Yang S, Zhong J-H, Wang T, Wang C, Chen F-Y (2010) Targeting Smad4 links microRNA-146a to the TGF-β pathway during retinoid acid induction in acute promyelocytic leukemia cell line. Int J Hematol 92(1):129–135 Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12(15):2424–2433

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Role of MicroRNAs in Cell Growth Proliferation and Tumorigenesis Srilekha Avvari, DKV Prasad, and Imran Ali Khan

Abstract

MicroRNAs (miRNAs) are a type of short noncoding RNA that regulates a broad range of biological processes, including cancer development. MiRNAs have been discovered to be highly dysregulated in cancer cells. MiRNAs are established in plants, viruses, and animals. Cell growth refers to an expansion in cell dimensions or mass buildup, while cell division indicates divide of two daughter cells for a mother cell. Cell proliferation is the process through which an increased number of cells are produced by cell division. Previous data confirmed as miRNAs have a role to play in tumor cell pharmacoresistance through the targeting of drugresistant genes or cell, cell, and apoptosis genes. This chapter describes how miRNA affects cancer by its function as oncogenes and tumor suppressors. In conclusion, this chapter confirms the importance of miRNA in cell growth and proliferation in numerous cancers and cancer-specific pathways. Keywords

MicroRNA (miRNA) · Cancer · Cell growth · Proliferation · Tumorigenesis

S. Avvari Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad, India D. Prasad Department of Biochemistry, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India I. A. Khan (*) Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Prasad, P. Santosh Sushma (eds.), Role of MicroRNAs in Cancers, https://doi.org/10.1007/978-981-16-9186-7_3

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MicroRNA and Cell

MicroRNAs (miRNAs) are identified in viruses, plants, and animals, composed of 23 nucleotides and double-stranded DNA molecules. The major function of miRNAs is to regulate the gene expression of the cell/cellular receptor through degradation or prevention of mRNA target molecules due to untranslated region binding sequence (Balusu et al. 2016; Bernardo et al. 2015). MiRNA-specific targets have partial complementary homology with miRNAs, and mutations in the 30 UTR of target transcripts can help to avoid miRNA-protein interactions by altering crucial target residues (Fabian et al. 2010). By altering the expression of the target transcript, miRNAs can influence many distinct signaling and metabolic processes, including proliferation, differentiation, and death (Inui et al. 2010; Bueno et al. 2008; Foshay and Gallicano 2007). Cell growth in several organisms was thoroughly investigated, and new regulatory pathways have been identified. However, cell growth is related with the fusion portion of the genital process that resembles or covers the entire cell width (Eckert et al. 1997). For the preservation of cell homeostasis and cell proliferation, the management of cell growth and division is crucial in a cell. Deficiencies in these mechanisms can eventually lead to aberrant cell development and cancer. While cell growth and division are two functionally independent processes, all cells need to produce descendants and link closely (Fig. 3.1). Cell growth refers to an expansion in cell dimensions or mass buildup, while cell division indicates divide of two daughter cells for a mother cell. Cell proliferation is the process through which an increased number of cells are produced by cell division. Two unique cell types are present in eukaryotic cells: meiosis-I is the division in which the parental cells produce two daughter cells with a mother cell code that is half of the genetic information, which originates in the gametes, and in mitosis-II, mother cells replicate a couple of identical daughter cells. In the cell division, cell growth and cell cycle regulation are closely interrelated (Fig. 3.2) (Rhind and Russell 2012; Kaldis 2016). Howard first characterized the cell cycle and its many phases in 1951. However, later on, studies documented that the cell cycle is highly preserved and organized and

Fig. 3.1 Normal process of cell, cell growth, and cell division

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Fig. 3.2 A clear picture of cell cycle

culminates in growth and division of cells. Many regulatory mechanisms that allow or limit the course of cell cycles are strictly controlled (Gali-Muhtasib and Bakkar 2002). Interphase, mitotic phase, and cytokinesis are the three stages of the cell cycle. Oncogenes may induce cell proliferation and apoptosis. With somatic cell proliferating, positive and negative signals control the course of the cell cycle. The common morphological aspects of apoptosis and mitosis include cellular recession, chromatin condensation, and membrane blebbing. In addition, genes like p53, RB, and E2F, both in the cell cycle and in apoptosis, were demonstrated to participate. Therefore, to maintain tissue homeostasis, the balance between apoptosis and proliferation is strictly required (Alenzi 2004). The normal course of cell cycles, as it defines body shape and growth, tissue renewal, and senescence, is a vital duty for any multicellular creature, also critical to reproductive function. Dysregulation of the progression of cell cycles to uncontrollable cell proliferation, on the other hand, is a characteristic of cancer (Urrego et al. 2014). Tumorigenesis is caused by a disruption in the cell cycle, which results in uncontrolled cell growth. Uncontrolled proliferation is a distinctive characteristic of cancer cells. Understanding the molecular relevance of cell cycle and checkpoint defects in cancer, as well as manipulating these regulatory mechanisms, provides insight into new therapeutic options (Golias et al. 2004).

3.2

Cell Growth and Proliferation

Cellular growth, proliferation, and differentiation are essential functions that underlie development as well as tissue regeneration or remodeling in the mature organism (Stachowiak et al. 1997). Cell growth may refer to cell proliferation and cell division.

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Cell development may also imply a rise in cell volume without cell division. Cell growth will occur when the overall rate of cell development is greater than the overall rate of cell decomposition. Living cell is, similarly, a knowledge-processing device, collecting information from its surroundings and determining what reactions are most suitable under the context. It could expand and divide, each cell splitting to create two cells, more cells, and so on. There is the aim of understanding cell biological molecular pathways that control these decisions (Tyson and Novak 2014). Because of the cells’ lack of cell-autonomous uptake of nutrients, multicellular organisms don’t directly perceive and scavenge nutrients in the environment. Nutrient uptake is principally controlled by growth factor signaling in animal cells (Zhu and Thompson 2019). Otto Warburg reported a fundamental observation in the 1920s that quickly spreading ascites utilize glucose, a characteristic known as Warburg effect, rather than totally oxidizing, as glucose-derived carbon in the lactate at unusually high rates compared with ordinary cells (Warburg 1925, 1956a). In 1956, Warburg hypothesized the permanent disruption of oxidative metabolism in tumor cells, which resulted in a compensatory rise in glycolytic stream (Warburg 1956b). After first cell divisions have occurred, the freshly developed zygote starts to distinguish, indicating that permanent improvements in the pattern of gene expression and cell activity are taking place. At this stage, cell proliferation becomes independent of cell-type differentiation. Cell division is more prominent in undifferentiated cells than it is in segregated cells. Normal cell proliferation is characterized by a balance of cell in growth, division, differentiation, and death, whereas defective cell proliferation is characterized by excessive over-proliferation and cell accumulation. Cell proliferation and differentiation are common throughout the phases of embryonic and postnatal growth but often occur in adults. It is now understood that cell proliferation and differentiation are dynamic operations, and there are no single master genes or switches that can regulate either process. Proliferation and distinction are regulated by many regulatory chemicals and molecules. Any of the regulating molecules involved in growth and development of some cell types have been established (Oshima and Campisi 1991). Cell size not only relies on cell development; it also depends on the proportion of cell growth. During cell replication, cell size may change to sustain a roughly stable population (Björklund 2019). Cell proliferation plays a key role in degenerative diseases, where cells are insufficiently replicated and over-proliferated. Cancers, rheumatoid arthritis, and pulmonary fibrosis are among of the frequent diseases caused by uncontrolled growth. The total cell proliferation process takes place through many phases of the cell cycle. A combination of cell intrinsic and extrinsic interactions and variables regulate the cell cycle and, on the other hand, cell proliferation. Certainly, the cells’ growth factors, enzymes, and genes are common factors (Faguet 2008). Growth and division of cells are linked to cell proliferation, which is regulated by cell division and cell death by cell differentiation. In natural tissues, cell proliferation is typically limited to cells that create new tissues, and most tissues contain preventive proliferating cells. Cancer generally has unregulated cell proliferation, and many anticancer therapies have been listed in the film. A number of approaches were demonstrated in Fig. 3.3 for cancer cell proliferation (Mohanta et al. 2019). Cell proliferation is the

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Fig. 3.3 Similar strategies were seen for the proliferation of cancer cells (Mohanty et al. 2019)

mechanism that results in an increase in the number of cells which, by cell death or differentiation, is characterized by a compromise between cell division and cell loss. When it comes to cell division, cell growth may also apply to an expansion of cell volume that takes place without cell division and without a rise in cell numbers (Guo and Hay 1999; Oppenheim 1991). In a study of the antiproliferative capability of the miR-15a-16-1 community, the first established interrelationship between

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microRNAs and cellular cycle control was discovered. Both clusters transmit two mature miRNAs that have virtually same sequences (miR-15 family). Surprisingly, the miR-15a-16-1 cluster has been identified as a target of mutations in chronic lymphocytic leukemia cells (Calin et al. 2002; Bueno and Malumbres 2011). Two unique cell types are present in eukaryotic cells: meiosis-I is the division in which the parent cells produce two daughter cells with a mother cell code that is half of the genetic information, which originates in the gametes, and in mitosis-II, mother cells replicate a couple of identical daughter cells (Rhind and Russell 2012; Rodrigues et al. 2018).

3.3

Role of MiRNAs in Tumorigenesis and Cancer

There are several roles that miRNAs have in the cellular system. Human malignant tumors, like cancer, contain a significant number of abnormal-expressing genes, and tumorigenesis is likely. This is higher in primary tumors in the gastric stomach and even in all cell lines in gastric cancer that may participate in the gastric cancer processes (Jiang et al. 2015). It is widely recognized that miRNAs take part in numerous processes, including apoptosis, proliferation, and pathways guided by receptors, etc. MiRNAs are a major challenge to direct RNA-based treatment for target tissues, their stability, and efficacy. For the treatment of miR-15a-16-1 cancer, apoptosis in MEG01 leukemic cells contributes to tumor growth and inhibits tumor growth, whereas the silence of oncogenic miR-21 with anti-insensitive oligonucleotides leads to proapoptotic and antiproliferative in vitro responses in various model cells, reducing tumor production and metastatic potential in vivo. miR-34a temporarily inhibits the development of human colon cancer when subcutaneously given in atelocollagen complexes, which has recently been shown to be a highly effective system to deliver small RNA molecules in vivo into cancers. miR-34, one of the best-known p53-bottom-function tumor suppressor miRNAs, is a gene that includes cell cycle arrest, cellular senescence, and apoptosis. As defects in p53 in the majority of human cancers (>50%) are combined, miR-34 replacement therapy provides a clear clinical promise for patients with solid tumor as therapeutic effective. The inhibition of proliferation of cancer cells and the induction of adrenolytic virus vector tumor-specific apoptosis have mediated miR-26a delivery to the HCC119 mouse model. After miR-133 overexpression and decreased left ventricular cardiac myocytes in number, fetal expression was also reduced markedly (Ahmad et al. 2013).

3.4

Influence of MiRNAs in Cell Growth and Proliferation in Various Cancers

Cell proliferation is a frequent process in which the parent cell divides into two cells for the daughter. MiRNA dysregulation has been associated to cancer hallmarks such as maintaining proliferative signaling, evading growth suppressors, resisting

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cell death, activating invasion and metastasis, and initiating angiogenesis. In an increasing number of research, miRNAs were identified as potential biomarkers for human cancer diagnostics, prognostics, and treatment goals or strategies (Fouad and Aanei 2017; Hanahan and Weinberg 2000). The disruption of cell cycle regulations, leading to unregulated cell growth, is connected with the carcinogenesis which is also caused by overactive signaling pathways that stimulate cell proliferation. The development of cell growth is regulated in normal tissue to prevent aberrant expansion. During neoplastic procedure, mutations and epigenetic processes such as miRNAs occur. The ability to infiltrate and metastasize causes an increase in cancer cell survival and proliferation (Feitelson et al. 2015). Numerous studies have demonstrated the significance of miRNAs in cell cycles and proliferation regulation (Hwang and Mendell 2006; Favreau et al. 2015; Li et al. 2014; Lin et al. 2016; Wang et al. 2017). MiRNAs are transcribed as primary miRNAs (pri-miRNAs), which are then processed in the core by RNase III Drosha endonuclease to produce a second precursor (pre-miRNAs) with 80 nucleotide stem loops (Soliman et al. 2018). Extensive studies carried out in previous years supported miRNAs’ significance in physiology as well as in numerous disorders, including cancer, such as regulating cell cycle, developing the immunity, cell proliferation, and cell differentiation (Schratt et al. 2006; Berenguer et al. 2013; Matysiak et al. 2013; Nana-Sinkam and Croce 2013; Peng et al. 2013). Gene expression profiling studies revealed alterations in miRNA expression across a wide range of human situations. Functional studies frequently connect miRNA dysregulation to disease progression as a causal cause (Hammond 2015). MiRNAs have also been shown to have a role in epithelial-mesenchymal transition (EMT) and cancer stem cells that are critically related to metastasis and drug resistance (Lu et al. 2005; Wellner et al. 2009). Oncogenes (oncomiRs) and oncosuppressor genes have been hypothesized to separate into two different classes of miRNAs (oncosuppressor-miRs). Oncogenes and oncosuppressor can be differentiated based on the level of their expression: some miRNAs with extremely high expression can act as oncogenes, whereas those with lower expression function as oncosuppressor (Mavrakis et al. 2011). So far, a lot of literature on the effects of miR-155 in cancer formation have been published (Table 3.1). For example, β-cell lymphomas (Eis et al. 2005), gastric MALT (Saito et al. 2012), and lung cancer (Zang et al. 2012) have showed high expression of miR-155 as an oncogene, while Burkitt adult lymphoma and melanoma have showed low expression as an oncosuppressor gene (Metzler et al. 2004; Levati et al. 2011). miR-155, which has a role in the hematopoietic malignancies oncogenesis, was characterized at first as overexpressed in β-cell lymphoma and lymphocytic leukemia (Eis et al. 2005). A study by Kong revealed that miR-155 overexpression can encourage development and angiogenesis in breast cancer by focusing mainly on VHL mRNA 30 UTR (Kong et al. 2014). MiRNAs, on the other hand, have been proposed to have a role in oncogenesis since they can operate as tumor suppressors, as in miR-15a and miR-161, or as oncogenes, as in miR-155 or members of the miR-17–92 cluster (Calin and Croce 2006). Both the miR-15 and miR-16-1 work for tumor suppressor by causing apoptosis through the suppression of Bcl-2, an overexpressed antiapoptotic protein

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Table 3.1 miR-155 as an oncogenes and tumor suppressor genes (Chen et al. 2014)

in malignant, nondividing B cells and some solid malignancies. miR-15 and miR-161 embolization in mice resulted in symptoms comparable to those found with chronic lymphocytic leukemia in humans suggesting the relevance of these two miRNAs in tumor suppression (Cimmino et al. 2005). The miR-17-92 is a standard example of a region amplified in the lungs and other malignant diseases at chromosome 13q31 (Hayashita et al. 2005). miR-155 is one of the most extensively researched miRNAs in autoimmunity. T, B, and dendritic cells are among the many immune cells for which miR-155 has essential regulatory activities. It has also been associated with the development of a number of autoimmune disorders due to abnormal miR-155 expression (Leng et al. 2011). The miRNA profiling indicated higher expression of miR-155 in different tumors and its manifestation was connected substantially with poor survival in individuals with pancreatic cancer (Greither et al. 2010). MiRNA is a typical and multifunctional miR-155 has captured the research interest and plays a vital role in a variety of diseases including hepatic carcinoma, leukemia, lung cancer, and breast cancer (Zhang et al. 2012; Faraoni et al. 2012; Yang et al. 2013; Zonari et al. 2013). Among the known oncomiRs, miR-155 is an important entity and one of the most often upregulated miRNAs in the development of leukemia, breast, pulmonary, and stomach tumors. It is an important focal point for diagnosis, prognosis, and therapy. While experimental evidence suggests that miR-155 is overexpressed in malignant tumors, the precise mechanism of miR-155 action remains uncertain. The miR-155 is one of the most important tumor promoter, consisting of the β-cell integration cluster (BIC), also known as MIR155HG (miR-155 host gene). The miRNA-based gene treatment options could be an effective way to stop tumor development. The miRNAs such as let-7, which has been found to adversely influence RAS oncogenes, and miR-15 and miR-16, which have been proven to negatively control BCL2, are prospective cancer therapeutic possibilities (Teng and Papavasiliou 2009; Sandhu et al. 2012; Tili et al. 2010; Donnem et al. 2011; Chen et al. 2015; Haasch et al. 2002). Several studies have demonstrated that miRNAs play a role in tumor cell drug resistance by targeting drug-resistant genes or influencing cell proliferation, cell cycle, and apoptosis genes. A single miRNA usually affects multiple genes and has regulatory effects particular to the tissue. According to the Si et al. review, miRNAs

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play a role in the control of drug resistance in cancers such as breast, lung, ovarian, pancreatic, and colorectal, and the causes of miRNA dysregulation are being studied. Another conclusion was that miRNA activities in drug resistance will help to develop better strategies for efficiently regulating them, paving the way for better clinical translation of miRNAs and a promising strategy in the field of cancer treatment (Si et al. 2019). MiRNA is seen as a possible biomarker to track CRC progression despite advancements in early checkups, diagnosis, and prediction CRC events (Dave et al. 2019). Reduced expression of miRNA clusters has been linked to the development or progression of CRC (Cheng et al. 2018).

3.5

Regulation of MiRNAs and Its Pathways

By suppressing numerous secreted signaling proteins, miRNAs can alter the signaling pathway. In multiple signaling pathways, the RAS is a signaling protein, and its overexpression frequently transforms ontogenically. The human RAS 30 UTL contains several more locations which allow let-7 to regulate RAS expression. Wnt, BMP, SHH, and Notch are some of the reported signals that play a significant part in the molecular processes of cell’s life, but these pathways, which control the proliferation of cells and differentiation in normal cell, change nearly inevitably in cancer. Certain cancer-related pathways influence directly the expression of particular miRNA genes (Liu et al. 2007). Yoo et al. have found a relation with LIN-12/ Notch pathway of communication links directly connected to the miRNA-61 gene and supports its precursor cell vulva formation during the C. elegans (Yoo and Greenwald 2005). EMT is known to be a transformed growth among the various signaling pathways which are TGF-β, Wnt/β-catenin (Hh), Notch, fibroblast growth factor receptor (FGFRs), and nuclear factor kappa-B (NF-kB). These include more clearly the cellular adhesion linkage, Wnt/β-catenin route, and EMT (Lei et al. 2020).

3.6

MiRNAs Modifications in the Wnt and b-Catenin Signaling Pathways in Cancer

EMT is a pathology that is largely connected with metastases of the tumor with documented studies showing Wnt signaling via Snail1 and Zeb1. Furthermore, miRNAs, such as miR-410, were involved by activating the canonical in vitro signals of Wnt to promote the development, migration, and invasion of non-small cell lung carcinoma. Tumorigenesis in the field of brain cancer, colorectal breast cancer, liver cancer, and other types of cancer has been regulated by a network of miRNAs and Wnt signaling pathways. The miR-374a overexpression resulted in nucleus β-catenin stability and accumulation of 4 T1 and MCF7 cell lines of brain cancer. According to the discoveries, miR-374a may cause APC or one of the other components of the destruction complex to degrade, hence increasing the

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Fig. 3.4 Role of the Wnt/miRNA network in the control of cancer stem cells (Onyido et al. 2016)

transcription of LEF/TCF4 into the nucleus (Medici et al. 2008; Zhang et al. 2016; Aslakson and Miller 1992). The cancer stem cells have many pro-cancer properties such as chemoresistance and tumorigenic and metastatic activity not shown by their normal counterparts in the stem cells shown in Fig. 3.4. Previous study has demonstrated that miRNAs influence EMT by targeting the Wnt/β-catenin signaling pathway. During EMT, the miRNA was drawn by a significant number of victims as a tumor suppressor or oncogene. Elucidating miRNA activities in EMT control may aid in the identification of potential therapy strategies (Lei et al. 2020).

3.7

Role of the miTALOS Tool in Investigating MiRNA-Mediated Signaling Pathway Regulation

MiRDB is an online resource miRNA target prediction that gives precompiled information on individual miRNA regulators. MiRGator offers functional annotation of miRNA targets as well as route mapping of individual miRNAs. DIANA-mirPath combines miRNA targets into pathways in the Kyoto Encyclopedia of Genes and Genomes and provides three unique target prediction tools. However, these pathways have the limited access toward the tissue-specific expression patterns. Due to the extremely tissue-specific expression patterns of miRNAs and target transcripts, tissue-specific gene expression must be incorporated in the analysis of miRNA regulation in biological pathways. miTALOS is the first publicly available resource tool that merge tissue and route filters in order to restrict functional analyses. Target enrichment and proximity analysis are part of miTALOS. The extensively employed enrichment approach infers miRNA-pathway correlations based on the number of target genes in a specific pathway. miTALOS evaluates a

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multifunctional enrichment score by applying miRNA-mediated control of the pathway via the total number of miRNA targets in a given signaling pathway. The enhancement scores assumes, high quantity of target transcripts, that miRNAs signaling pathways for influencing the cell-based functions. The added value is then determined by the target gene fraction in comparison with the anticipated number of target genes on a specific pathway. Signaling pathways are often activated by distinct stimuli in separate cascades. As the full pathway is focused on the enrichment method, the subcascade relationship between miRNAs and signaling pathways is overlooked. MiRNAs target the signaling cascades at the beginning of the pathway. When looking for pathways that include proteins that work closer to the targeted miRNA, proximity measures were used. The signaling pathway was estimated the distances between all pairs of targets. The selection of the target’s minimum distance is made, and the proximity score is determined as the average of all the target’s minimum distances (Kowarsch et al. 2011).

3.8

Conclusion

Different molecular mechanisms and cellular goals have been identified, including their capacity to control and enhance proliferation and progression of cell cycles. MiRNAs have a role to play in tumor cell pharmacoresistance through the targeting of drug-resistant genes or cell, cell, and apoptosis genes. This chapter describes how miRNA affects cancer by its function as oncogenes and tumor suppressors. In conclusion, this chapter confirms the importance of miRNA in cell growth and proliferation in numerous cancers and cancer-specific pathways.

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The Impact of MicroRNAs in Cell Adhesion and Tumour Angiogenesis Gaurav Singh, DKV Prasad, Pinninti Santosh Sushma, and K. Sri Manjari

Abstract

MicroRNAs (miRNAs) are a class of non-coding RNAs of roughly 22 nt length that plays a salient and myriad role in gene expression and regulation. Altered miRNA expression profiles have been reported to contribute to the pathogenesis of diseases such as cardiac abnormalities and cancer development. Therefore, it is vital to ensure the optimal miRNA activity is maintained, and it is essential for cellular homeostasis, as altered function will cause exacerbated deregulation of the complex signalling networks that are regulated downstream by these miRNAs. Some classes of miRNAs have been shown to influence the regulation of cellular adhesion pathways, and associations have been found between miRNAs and the clinical outcomes of cancer. Angiogenesis is always putative targets for cancer therapeutics, and miRNAs can regulate many of the pathways of angiogenesis. In this short review, we briefly recapitulate the overarching mechanisms of miRNAs, their role in regulating cell adhesion molecules (CAMs) and their subsequent effect and significance in tumour angiogenesis and growth.

G. Singh Department of Biosciences, University of Milan, Milan, Italy D. Prasad (*) Department of Biochemistry, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India P. Santosh Sushma Biomedical Sciences Division, College of Community Health Sciences, University of Alabama, Tuscaloosa, AL, USA K. Sri Manjari Department of Genetics and Biotechnology, University College for Women, Koti, Osmania University, Hyderabad, Telangana, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Prasad, P. Santosh Sushma (eds.), Role of MicroRNAs in Cancers, https://doi.org/10.1007/978-981-16-9186-7_4

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Keywords

Angiogenesis · MicroRNAs · Cell adhesion molecules (CAMs) · Vascular disease

4.1

Introduction

Cell adhesion is a complex process by which cells communicate with each other by forming contacts or through the formation of specialized protein complexes. It involves both cell-to-cell interactions and also cell-matrix associations. Cell adhesion occurs from the interactions between cell adhesion molecules (CAMs) which are transmembrane proteins located on the cell surface (Lodish et al. 2003). Cell adhesion molecules are broadly classified into four major families of integrins, immunoglobulin superfamily, cadherins and selectins. They can further be subdivided into two classes based on their properties. Cadherins and immunoglobulins are homophilic in nature as they directly bind to the same type of CAMs on another cell. On the other hand, integrins and selectins are heterophilic CAMs that bind to different types of CAMs. Each adhesion molecule has a different function and recognize different types of ligands. Any defects arising in cell adhesion process can be attributed to defects in expression of CAMs. In multicellular organisms, intercellular adhesion bindings between CAMs allow the cells to adhere to one another by the formation of specialized structures called cell junctions. These junctions can be mediated by anchoring junctions, occluding junctions and channelforming junctions, whereas cells can interact with extracellular matrix molecules through focal adhesions. Alternatively, these junctions can be categorized into two types based on what interacts with the cell, namely, cell-to-cell junctions mediated by cadherins and cell-matrix junction mediated by integrins. Cellular adhesion plays a key role in the signal transduction networks that lie downstream of these cell adhesion molecules. Therefore, by extension, the deregulation of these adhesion molecules has been observed to play a crucial role in the causation of many human diseases such as the development of cancer (Guo and Giancotti 2004; Parsons et al. 2010), and this makes them an important area of research. Angiogenesis is defined as the process of capillary sprouting from pre-existing vasculature and is most strongly induced by low tissue oxygen tension (hypoxia), although can be promoted by other biological processes (Warmke et al. 2018). Cancer is a complex disease which can be caused by varied number of factors like genetics, environmental damage and food quality. Although angiogenesis is a vital process in normal growth and development, aberrant angiogenesis is a fundamental step and central to many angiogenic diseases such as age-related macular degeneration (AMD) (Wang et al. 2016a, b) and rheumatoid arthritis (RA) (Chen et al. 2017; Elshabrawy et al. 2015; Jiang et al. 2016). Aberrant angiogenesis is also critical for cancer metastasis (Folkman 1995; Li et al. 2015, 2017; Shen et al. 2017; Xu et al. 2017). MiRNAs involved in regulating normal physiological processes are also involved in cancer pathogenesis. They suppress gene expression by binding to the 30 -UTR region of their target genes and can thus act as oncogenes or tumour

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suppressors. Various roles of miRNAs in anti-angiogenic treatment have emerged which show promise towards developing novel approaches to treat metastatic cancers. In this review, we will summarize some of the current knowledge regarding the roles of miRNAs in regulating cell adhesion molecules and tumour angiogenesis. We will first recapitulate the overarching mechanism of miRNA interactions, followed by looking into new research highlighting that miRNAs are capable of controlling the expression levels of many crucial cell adhesion molecules making it apparent that miRNAs play imperative key roles in organizing diverse aspects of the biochemical pathways that govern normal cellular adhesion (Valastyan and Weinberg 2011). Deregulation of some of these miRNAs has also been found to contribute to the pathogenesis of human diseases, like neoplastic development leading to subsequent metastatic progression. Cumulatively, these findings strongly suggest towards evidence that miRNAs are implicated in our understanding of their role in cell adhesion processes and molecules. In addition, research also suggests that certain miRNAs manifest themselves as attractive molecular targets for the development of novel drug targets, particularly in diseases caused by deregulated cell adhesion processes.

4.2

MiRNA Overview

MiRNAs have a variety of mechanisms by which they mediate gene regulation. They control the expression of one or more target mRNAs and can also be regulated by multiple miRNAs. The 50 region of miRNA largely contributes to the specificity and activity in binding targets. The interactions between miRNA and mRNA are usually restricted to the feeder sequence around the 50 terminus in animals. This short six to eight nucleotide sequence is conserved among species, and slight alterations in the sequence read alters the spectrum of putative targets. MiRNAs also contain interaction sites with mRNA 50 -UTR and 30 -UTR motifs through their 30 - and 50 -end sequences. Recent studies have suggested that methods integrating factors such as 50 -UTR and protein repression level into the sophisticated target prediction processes greatly improved the possibility of identifying real targets (Maragkakis et al. 2009; Stark et al. 2007). Most studies have highlighted and provided evidence of the role of miRNA-dependant gene repression; some have also reported the upregulation by miRNA-mediated translational activation and gene expression. Upregulation of gene expression by miRNAs has been observed in quiescent cells, wherein nuclear microRNP, comprising AGO2 and FXR1-iso-a, associates with specific mRNAs, leading to their upregulated expression in immature, folliculated oocytes and in human G0 cells (Truesdell et al. 2012). As another example, miR-206 upregulates Kruppel-like factor 4 (KLF-4) in non-tumour cells (Lin et al. 2011). Therefore, miRNA-mediated upregulation of gene expression can occur under specific and is specific to cell types and cell features.

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Based on our current understanding, miRNA-dependant post-transcriptional gene regulation broadly adheres to two distinct mechanisms based on the features of the target recognition by miRNAs. The target can be cleaved at a defined position relative to the miRNA complementary sequence (Hutvágner and Zamore 2002) followed by the translation of the target RNA which may be inhibited, without triggering a sequence-specific mRNA degradation. The biological outcome of miRNA-mRNA interaction can be altered by several factors that contribute to the binding strength and repressive effect of a putative target site and can have several repercussions (Carroll et al. 2014). Gene silencing mediated by miRNA can occur at pre-translational, co-translational and post-translational steps and can impart direct and/or indirect effects on translation machinery. mRNA degradation can occur by either 30 -end deadenylation or by 50 -end decapping by enzymes such as DCP1/2. Binding of micro-ribonucleoproteins (miRNPs), complexed with accessory factors, to mRNA 30 -UTR can also induce deadenylation and decay of target mRNAs (Wu et al. 2006). Recent evidence also indicated that processing cytoplasmic foci, known as P or GW bodies, play a key role in mRNA degradation and translation inhibition. Target mRNAs associated with P bodies can either be degraded or returned to translation, and this dynamic equilibrium between polysomes and miRNPs determine the rate of mRNA expression and repression. The repression can also occur at post-initiation phases of translation, due to either staggered elongation rates or ribosome ‘drop-off’ (Petersen et al. 2006; Maroney et al. 2006). Cumulatively, these findings propose a possible model wherein target mRNA is sequestered from the translational machinery and undergoes both degradation and/or stored for subsequent processes (Eystathioy et al. 2003; Andrei et al. 2005; Sen and Blau 2005; Jalkanen et al. 2007).

4.3

MiRNA and Role in Cell Adhesion

Cell adhesion is defined as the method or process by which cells interact with each other and attach to neighbouring cells, making use of specialized molecules of the cell surfaces they associate with. Interaction between a cell and its environment and/or with other neighbouring cells is governed by cell surface proteins. This process occurs either through a direct cell surface-to-cell surface contact such as in the case of cell junctions or alternatively via an indirect interaction, whereby cells attach to surrounding connective material comprising of large proteins and polysaccharides, also known as an extracellular matrix which acts like a connective scaffold that holds cells in a defined space. Cells make this connection by the aid of transmembrane proteins called cell adhesion molecules (CAMs). Adhesion molecules are generally divided into four groups: the immunoglobulin superfamily (IgSF), integrins, selectins and cadherins. Certain enzymes such as vascular adhesion protein 1 (VAP-1) have shown a role in cell adhesion (Takai and Nakanishi 2003). Members of the immunoglobulin superfamily (IgSF) include vascular and neural cell adhesion molecules like VCAM (VCAM-1, MadCAM, NCAM) and are

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expressed mainly by immune cells and endothelial cells; intercellular adhesion molecules (ICAM) like ICAM-1, ICAM-2 and ICAM-3; and the nectins and nectin-like (Necl) family of proteins which are expressed in a number of cell types where they are involved in formation of cell-cell adhesion and formation of stable junctions via cadherin (Samatov et al. 2017). They mediate initial cell-cell connections either via nectin-nectin or nectin-Necl associations and establishing a nectin-afadin-mediated link to the actin cytoskeleton (Parsons et al. 2010). The integrin family of CAMS acts as receptors for ICAMs and VCAMs. Integrins are heterodimeric proteins which consist of an alpha and a beta chain that mediate leukocyte adherence to various cell-cell interactions. Different leukocytes express varied sets of integrins which provide specific binding capacity to different types of CAMs expressed along the lining of the vascular endothelium. The three selectin family members include endothelial (E)-selectin, platelet (P)selectin and leukocyte (L)-selectin and are involved in the adhesion of leukocytes to activated endothelium cells. The adhesion is initiated by weak non-specific interactions that produce a characteristic ‘rolling’ motion of the leukocytes over the surface of endothelial cells. P- and L-selectins in conjunction have been implicated in the mediation of these initial interactions. This is followed by further strengthened interactions eventually leading to extravasation through the blood vessel walls into lymphoid tissues. An epidermal growth factor (EGF)-like carbohydrate recognition motif is present in the extracellular domain and varying numbers of a short, repeated domain related to complement-regulatory proteins (CRP). There occur some proteins that are functionally similar and classifies as CAMs due to their involvement in strengthening the association of T cells with antigenic cells or target cells and/or in the activation cascade of T cells. CD44, another type of adhesion molecule, is a glycoprotein upregulated under dynamic microcirculation conditions and has been implicated in lymphocyte homing (Parsons et al. 2010), whereby lymphocytes recirculate the lymphatic system back into circulation loaded with antigen. This cell surface protein is involved in various cell-to-cell and cell-to-matrix interactions and in migration and is also known as a stem cell marker for colon cancer cells (Parsons et al. 2010). Variant forms of CD44 may play an important role in tumour metastasis. Cell adhesion molecules are critical to various cellular processes and responses and also play important roles in various diseases and disease states. New studies on miRNA networks and roles at controlling the expression levels of many crucial cell adhesion molecules make it apparent that miRNAs play imperative key roles in regulating the biochemical pathways that govern cellular homeostasis and adhesion. Deregulation of these miRNAs has been a contributing factor to the pathogenesis of multiple human diseases. Cell adhesion is coupled to the actin cytoskeleton either to the actin cytoskeleton of a neighbouring cell or to specific components of the surrounding extracellular matrix. Therefore, cell adhesion occurs via the concerted actions of cytoskeletal regulatory proteins, cell-to-cell/cell-to-matrix adhesion molecules and ECM proteins (Heasman and Ridley 2008). A major node that oversees actin polymerization and depolymerization is comprised of members of the Rho superfamily of small GTPases (including the Rho, Rac and Cdc42

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subfamilies) (Valastyan et al. 2009). The miR-31 and miR-133 both suppress expression of RhoA in different tissue types (Carè et al. 2007), and miR-34 regulates the mRNA encoding β-actin (Thiery et al. 2009) which clearly shows that miRNAs play a role in regulating relevant biochemical pathways that control the expression levels of numerous cytoskeletal regulatory proteins (Fig. 4.1). Also, we know that E-cadherin is the predominant adhesion molecule present on all epithelial cells (Hao-Xiang et al. 2010). E-cadherin can be targeted by the miRNA miR-9 (Ma et al. 2010), and direct regulation of the E-cadherin-encoding mRNA by miRNAs is important in determining E-cadherin levels (Wang et al. 2010). E-cadherin have the capacity to regulate the expression of transcription factors zinc finger E-box-binding proteins ZEB1 and ZEB2, which can repress transcription from the E-cadherin gene, and miR-192 and miR-205 (Suárez et al. 2010) have been shown to bind the 30 -UTR of ZEB1 and ZEB2 and therefore mediate the posttranscriptional downregulation which in turn increased E-cadherin expression levels. miR-31 is an interesting miRNA as it can pleiotropically regulate mRNA targets that are involved in a variety of distinct cellular processes relevant for overall cell adhesion status (Hu et al. 2010). It can modulate both cytoskeletal regulatory factors, cell-matrix adhesion receptors and cell-cell adhesion molecules. Similarly, intercellular adhesion molecule 1 (ICAM-1) is a target of miR-17, miR-221, miR-222 and miR-339 (Hu et al. 2010; Ueda et al. 2009; Fang et al. 2010). Likewise, miR-10a and miR-126 control the expression of vascular cell adhesion molecule 1 (VCAM-1) (Harris et al. 2008; Rojas and Ahmed 1999). This indicates that miRNAs can regulate the expression levels of mRNAs which encode a different cell-cell adhesion factors, thereby reiterating the roles of these small RNAs in overseeing pathways central to cellular adhesion processes. Tumorigenesis is another process where cell adhesion molecules are intricately involved (Gahmberg et al. 1999). The process of tumorigenesis occurs with changes in cellular adhesivity which disrupts normal tissue architecture followed by angiogenesis providing the growing tumour with a blood supply. During metastasis, cells detach from the primary tumour, attach to a blood vessel wall and, by travelling through the bloodstream, attach to a vessel wall at a secondary site in order to establish a new tumour. CAMs also play a role in the establishment of the bloodbrain barrier and facilitate its penetration by immune cells. Trans-endothelial migration of leukocytes is an example of one of the many roles of adhesion molecules (Etzioni et al. 1999; Kaltner and Stierstorfer 1998; Van Rooij et al. 2008). The first step entails the rolling of the circulating leukocyte along the walls of the endothelial cells, and this is mediated by selectin. This is followed by the contact activation of cell surface adhesion by specific ECM proteins and inflammatory cytokines. The third step is the firm adhesion where the leukocyte firmly attaches to an endothelial cell, and this involves arrest of the rolling process and spreading over the endothelial surface. This is done by integrins and their ligands. Lastly, transmigration of the leukocyte through adjacent endothelial cells takes place by a process called diapedesis. PECAM-1 is a crucial player in this step, and this migration demonstrates cooperative interaction between leukocyte and endothelial cell adhesion molecules.

The Impact of MicroRNAs in Cell Adhesion and Tumour Angiogenesis

Fig. 4.1 MiRNA-mediated regulation of cell adhesion molecules: illustration showing some of the known miRNAs that modulate expression of different kinds of molecules. Blood miR-1185 exacerbates E-selectin and VCAM-1 expression (mechanism unknown), and miR-126 targets the tissue factor in monocytes and inhibit VCAM-1 and fibrinogen expression in endothelial cells indirectly

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The altered activity of some adhesion-associated miRNAs has also been found to contribute to the pathogenesis of primary tumour development and metastatic progression. The miR-10b, miR-31 and miR-335 contribute to metastatic progression in tumour models (Valastyan and Weinberg 2009). Some are also known to target key effectors which belong to more than one of the four major classes of cell adhesion molecules such as miR-17, miR-29, miR-31 and miR-200 (Valastyan and Weinberg 2009; Ventura and Jacks 2009). These support the notion of the profound effects that certain miRNAs have on cellular phenotypes. Moreover, when taken together, the examples cited above provide substantial evidence that the altered activity of a number of adhesion-pertinent miRNAs contributes crucially to disease pathogenesis. The role of miRNAs in the regulation of cellular adhesion pathways is attributable to their capacity to pleiotropically target various integral components of each of the principal classes of molecules relevant to cell adhesion processes.

4.4

MiRNA and Tumour Angiogenesis

Angiogenesis is one of the fundamental hallmarks of cancer. Formation of new tumour-associated new vasculature is vital for delivering nutrients and supplying oxygen to growing tumours. The scope of this process extends to other processes like metabolic deregulation (Wang et al. 2015) and cancer stem cell maintenance (Lathia et al. 2011; Calabrese et al. 2007). Angiogenesis is a complex process by which new blood vessels are formed from pre-existing ones by sprouting, remodelling and expansion of primary vascular networks (Herbert and Stainier 2011). Angiogenesis originates from already existing vessels with the conversion of a previously inactive endothelial cell into a tip cell. This tip cell forms filopodia, and these filopodia probe the surrounding natural environment and are then invaded by the endothelial sprout, wherein the tip cell followed by the migrating column are formed by proliferating ECs. During endothelial sprouting stage, vacuoles are formed within stalk cells and fuse and give rise to the vascular lumen. Once the newly developed vessel is formed, it undergoes stabilization and maturation, and this process is mediated by intercellular adhesion and mural cell coverage. Under normal circumstances, following this morphogenesis, the vasculature becomes largely dormant. However, within tumours, there exists an angiogenic switch which remains activated and causes the continuous proliferation of new vessels (Hanahan and Folkman 1996). The angiogenic switch is regulated by pro-angiogenic and antiangiogenic signals which are induced by tumour cells (Baeriswyl and Christofori 2009; Bergers and Benjamin 2003). The turning on of pro-angiogenic signals or inhibition of anti-angiogenic signals defines the angiogenic switch as being switched on. Understanding the regulation of tumour angiogenesis is important to study the disease progression and to develop therapeutic strategies against cancer. Previous studies have elucidated the involvement of cell adhesion and CAMs as mediators of angiogenesis which begs to question if loss of cell adhesion either to matrix or adjacent endothelial cells is a critical step in the regulation of the angiogenesis system. E-selectin and soluble VCAM-1 are chemotactic to endothelial cells

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in vitro and angiogenic in rat cornea in vivo (Coultas et al. 2005). Leukocytes bind to endothelial cells with the release of cytokines, and this is followed by the subsequent shedding of CAMs from endothelial cells. The released molecules then bind to adjacent endothelial cells and cause direct angiogenic effect. The regulation of these angiogenic signals can also occur via the specific targeting of angiogenic factors and protein kinases. Pro-angiogenic miRNAs target VEGF family, and anti-angiogenic miRNAs induce the thrombospondin-1 (TSP-1) and hence regulate tumour angiogenesis. Angiogenesis remains a complicated and multistep process that involves a series of events that begins at activation, proceeds through a set of migration and proliferation profiles and is completed by the differentiation of endothelial cells followed by the ultimate reorganization into new tubular structures (Koch et al. 1995; Bentley and Chakravartula 2017; Betz et al. 2016; Li et al. 2012). Each step is controlled by numerous pro- and anti-angiogenic factors. Tumour cells secrete these factors in the surrounding environment to promote vessel growth. Angiogenesis has many endogenous stimulators like vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), IL-8, Notch ligands, angiopoietins (Ang1 and Ang2) and transforming growth factor-β (TGF-β) (Claesson-Welsh 2008). The VEGF includes VEGF-A type, B type, C type and D type and is the most important stimulator. The signal transduction of VEGF family of receptors requires three receptor tyrosine kinases (RTKs), namely, VEGFR-1, VEGFR-2 and VEGFR-3. While VEGF B and C/D types regulate embryonic angiogenesis and genesis of lymphatic vessels (Ferrara 2009), VEGF-A is a highly potent trigger for angiogenesis by signalling through VEGF receptor-2 (VEGFR-2) (Linderholm et al. 1998). VEGFR-2 mediates the mitogenic and chemotactic effects of VEGF in endothelial cells. VEGFR-2 is activated through autophosphorylation of tyrosine residues in the cytoplasmic kinase domain. This event is essential for EC migration and proliferation. Downregulated miR-497 expression was associated with increased angiogenesis (Wang et al. 2014) impairing the VEGFR-2-mediated PI3K/AKT and MAPK/ERK pathways. miR-542-3p and miR-543 are downregulated in tumour tissue, and the angiopoietin-2 inhibition is abolished causing promotion of tumour angiogenesis (He et al. 2014; Fan et al. 2016). miR-503 simultaneously downregulates VEGF-A and FGF2 demonstrating the anti-angiogenesis role in tumorigenesis (Zhou et al. 2013a). A curious case is that of miR-296 which is upregulated by VEGF-A and is found to be overexpressed in cancer tissue, and it ultimately enhances the protein levels of platelet-derived growth factor receptor (PDGF-R) and VEGFR-2. It does so by blocking their degradation by targeting the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) (Würdinger et al. 2008). miR-126 inhibits Spred-1 and PIK3R2 and directly targets VEGF-A, suggesting a putative role in tumorigenesis and growth by regulating the VEGF/PI3K/AKT signalling pathway (Zhang et al. 2013). The process of angiogenesis is regulated by pro-angiogenic and anti-angiogenic factors. Tumoural miRNAs can also be regulated in a VEGF-independent manner. Some miRNAs miR-503 (Zhou et al. 2013b), miR-214 (Shih et al. 2012) and miR-497 (Zhao et al. 2013) have been reported to target these pro-angiogenic factors in tumour cells, such as the fibroblast growth factor (FGF) and the hepatoma-derived

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growth factor (HDGF). Thrombospondin-1 (TSP-1) is an endogenous glycoprotein and anti-angiogenic factor (O’Reilly et al. 1994, 1997; Dameron et al. 1994). TSP-1 is encoded by the THBS1 gene and influences tumoural angiogenesis by exerting an effect on the endothelial cells (ECs). TSP-1 binds to its receptor CD36 and inhibits the activation of metalloproteinases (MMPs) which hinders the release of VEGF-A sequestered in the extracellular matrix (Rodriguez-Manzaneque et al. 2001). There is a general crosstalk between pro-angiogenic signals induced by growth factors and anti-angiogenic signals induced by TSP-1 and TSP-1-induced activation of CD36 which leads to inhibition of migration and induction of apoptosis (Dawson et al. 1997). TSP-1 in tumour cells is a reported target of several miRNAs like the miRNA-92 (Dews et al. 2006a), miR-182 (Amodeo et al. 2013) and miR-194 (Sundaram et al. 2011), thereby decreasing the overall secretion levels of TSP-1 secretion and as a consequence promoting tumour angiogenesis. miR-18a and miR-19 negatively regulate TSP-1 levels during Myc-induced angiogenesis (Dews et al. 2006b). In the case of endometrial cancer, a substantial correlation was observed between miR-17 and TSP-1 protein levels and also between miR-222 and VEGF-A (Ramón et al. 2011). A significant positive correlation between TSP-1 protein and miR-210 was observed, and this promoted angiogenesis in endometrial carcinomas (Ramón et al. 2011). miR-467 was identified as a translational suppressor of TSP-1 and is implicated in the control of angiogenesis in the presence of high levels of glucose (Bhattacharyya et al. 2012). In vivo angiogenesis models provided evidence that miR-467 promotes growth of new blood vessels, and TSP-1 was the primary mediator of this process (Bhattacharyya et al. 2012). The insulin-like growth factor (IGF) signalling pathway plays a critical role in the development and progression of various tumours. miR-126 exerts a repressive expression in tumour tissue and activates IGF1R on endothelial cells. This happens by two distinct pathways IGF1/IGF1R and/or the cleaved MERTK/GAS6 pathways, which exacerbate endothelial migration and angiogenesis (Png et al. 2011). Overexpression profiles of miR-181b elucidate inhibited cell proliferation, migration, and tumorigenesis by directly targeting IGF1R and its downstream signalling pathways, PI3K/AKT and MAPK/ERK1/2. In a similar manner, expression of both miR-148a and miR-152 is negatively affected in the tumour microenvironment, causing the lack of inhibition of IGFIR and IRS1, and thus their cascading downstream pathways activate tumoural angiogenesis (Xu et al. 2013). miR-26a-mediated inhibition of PIK3C2α deregulates the PI3K-Akt-HIF-1α-VEGF-A pathway, which is a prime cascade in tumour angiogenesis (Ma et al. 2016). Pro-angiogenic factors VEGF-A and HIF-1α target the mTOR kinase; an important observation was in the case of miR-18a, which inactivates mTOR and suppresses angiogenesis by deregulating the phosphorylation of mTOR substrates, S6K1 and 4E-BPl (Zheng et al. 2013). Similarly, miR-128 and miR-145 inactivate the mTOR pathway by inhibiting the rapamycin target p70S6K1 and suppressing pro-angiogenic factors such as HIF-1 and VEGF (Shi et al. 2012; Qing et al. 2012). The signalling cascade of phosphatidylinositol 3-kinase (PI3K)-AKT is a mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase (ERK) pathways. A wide variety of miRNAs (pro-/anti-angiogenic) exert control

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over these pathways. miR-126 is an endothelially localized miRNA which acts as pro-angiogenic over the targets of VEGF and FGF and promotes blood vessel formation by repressing the expression of Sprouty-related, EVH1 domaincontaining protein-1 (Spred-1) (Phoenix and Temple 2010). miR-26a and miR-218 inhibit the protein expression of the mRNA PIK3C2α (class II PI3Ks), and miRNA26a inhibits angiogenesis by downregulating VEGF-A through the PIK3C2α/AKT/ HIF-1α pathway (Chai et al. 2013). Another evidence is the role of miR-128 in targeting the EGF receptor (EGFR), and miR-128 also interacts with major subunits of the RTKs signalling pathways including PLCγ1 and PIK3C2A (She et al. 2014). Another miRNA, miR-145 directly represses RTKs signalling in human colon cancer cells by binding to the 30 -UTR of p70S6K1 and downregulating its posttranscriptional expression (Xu et al. 2012). The repression of miR-218 causes a significant upregulation of the activity of multiple RTK effectors, as a consequence of which, elevated RTK signalling and promoted the activation of HIF, most notably HIF-2α (Fig. 4.2). Hypoxia-inducible factors (HIFs) are a family of heterodimeric complexes comprised of an unstable α-subunit (three isoforms) and a stable constitutively expressed β-subunit. Both are hypoxia-inducible. The HIF-1α subunit is perpetually synthesized and degraded under low oxygen conditions, and this hinders the function of HIF-1 (Salceda and Caro 1997). HIF-1α is a target of many pro-angiogenic gene regulators; an example is the miR-22 which is a downregulated tumour suppressor and causes elevated HIF-1α levels (Yamakuchi et al. 2011). Similarly, overexpression of miR-107 causes HIF-1α inhibition and cascading inactivation of the downstream pathway. However, in tumours, this miRNA is downregulated and causes pro-angiogenic signalling (Yamakuchi et al. 2010). MiRNAs target HIF and therefore, also target HIF dependent transcription. This has an impact on all the cellular functions that are involved in the angiogenic pathways (Liao and Johnson 2007; Theodoropoulos et al. 2004). A long list of miRNAs targets the HIF complex, some examples being miR-20, miR-107, miR-199 and miR-519c. Overexpression of miR-519c results in decreased HIF-1α protein levels and reduced tube formation in the human umbilical vein endothelial cells (Cha et al. 2010), and miR-519 also binds to the 30 -UTR of HIF-1α and reduces tumour angiogenesis. miR-145 supresses the active isoforms of HIF-1α and HIF-2α (Zhang et al. 2014). On the contrary, miR-155 downregulates the Von Hippel-Lindau tumour suppressor (VHL) causing an increased overexpression of HIF-1α and excessive angiogenesis (Kong et al. 2014). miR-22 was reported to be an anti-angiogenic factor by supressing normal HIF-1α expression and repressing VEGF production during hypoxia (Yamaguchi et al. 2011). The miR-107 is expressed in human colon cancer cells and is overexpressed in tumour cells. This causes a suppression of tumour angiogenesis and tumour VEGF expression in mice, suggesting a miR-107-dependant p53 regulation of hypoxic signalling and tumour angiogenesis with HIF-1β acting as the putative target (Feng et al. 2011). Another important fact is to understand that a single mRNA transcript can also be regulated by multiple miRNAs in a combinational manner. This is evident because the miRNA seed sequence is generally between 6–8 bases and the 30 -UTR of the HIF-1α can bind many such miRNA,

Fig. 4.2 Different ways miRNAs mediated and regulate tumour angiogenesis: (1) miRNAs can influence the common signalling cascades that are involved in cell functioning of which endothelial cells are recipients. (2) Autocrine-derived miRNA from ECs can produce a protruding tip EC phenotype that leads to sprouting angiogenesis. (3) Specific types of miRNAs may also induce vasculogenic mimicry. (4) Dysfunctional tumour functions promote tumour motility and cell invasion of nearby ECs and promote tumour progression by co-opting existing vascular structures

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which ultimately determines its translational profile and homeostasis (Serocki et al. 2018). HIF switch is a phenomenon wherein the two major isoforms ‘switch’ roles in regulating the general tumour angiogenesis pathway. HIF-1α is the leading isoform in the case of initial hypoxia period, but after levelling of hypoxia, HIF-2α is upregulated, and HIF-1α is suppressed. Two specific miRNAs, miR-155 and miR-429, are induced by HIF-1α, but this leads to the downregulation of its own expression. This decrease causes a switch to HIF-2α signalling. miR-542-3p and miR-543 are downregulated in tumour tissues and promote tumour angiogenesis as their inhibitory effect on angiopoietin-2 ceases at low levels (He et al. 2014; Fan et al. 2016).

4.5

Clinical Implications and Future Perspectives

The role of miRNAs in tumour angiogenesis is critical to understand their therapeutic potential. Many miRNAs have been tested for specific tumours, and their expression profiles in cancer cells have been used to diagnose cancer such as miR-18a and miR-155 (Komatsu et al. 2014; Sochor et al. 2014). Some specific miRNAs like miR-26a are downregulated in tumour cells. Despite the development of reasonable number anti-angiogenic agents, their effectiveness has remained questionable, especially due to the lack of predictive biomarkers and drug resistance in the regulation of angiogenesis (Casanovas 2012; Jaszai and Schmidt 2019). The use of miRNAs in targeting of tumour angiogenesis with the use of antagomiRs and miRNA substitutes to combat the loss of expression of a tumour-suppressor miRNA into tumour cells has also been studied (Garzon et al. 2010). The use of anti-miR132, anti-miR-296 or miR-7 mimics has shown to strongly block angiogenesis and significantly reduces the tumour-induced strain in xenograft mouse models (Anand et al. 2010; Babae et al. 2014; Liu et al. 2011). Injecting modified liposomes with acetylated polyethyleneimine along with miR-125b into a tumour xenograft mouse model resulted in a decrease of VE-cadherin expression and the subsequent inhibition of tumour growth (Muramatsu et al. 2013). Significant advances have been made for the discovery of the miRNAs, which play a crucial role in the angiogenesis of a specific tumour type by altering a whole network of target proteins. Improved studies of the regulatory role of miRNAs in tumour angiogenesis and the potential of miRNAs as predictive biomarkers as therapeutics to target tumour angiogenesis will be the advent of new strategies in the fight against cancer. MiRNA expression profiles during the progression of many tumours are indicative of the use of miRNAs as prognostic biomarkers in cancer diagnosis and treatment. Moreover, treatments can be used alone or be coupled with current targeted therapies to downregulate angiogenesis. However, the clinical applications of miRNA-based therapies have had far fewer reported successes in preventing the effects of different angiogenesis-regulated miRNAs on tumour developing due to challenges posed by off-target effects, biological instability and toxicity and poor cellular uptake of miRNAs. The number of staggering discoveries in the past decade has paved the way for the use of miRNAs as the targeted therapy of the

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future, though there are some challenges including but not limited to tissue-specific delivery, minimizing the effects caused by off-target interactions and optimizing existing therapeutic protocols.

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Oxidative Stress Modulation with MicroRNAs in Cancers Srilekha Avvari, M. Rishitha, K. Sri Manjari, Subhadra Poornima, and Imran Ali Khan

Abstract

Cellular stress responses are very dynamic and enable cells to successfully resist various stresses that are essential to optimal cell homeostasis. The cellular stress response was recently influenced by a new type of RNA, called miRNAs. Oxidative stress (OS) is defined as a balance between the development and ability of the organ and cells to detoxify or minimize the damage caused by reactive oxygen species (ROS). The OS regulates major cellular responses by mediating signal transduction and regulating transcription factors and noncoding RNAs. Many studies have revealed that these oxidative stresses are able to regulate miRNA biogenesis and expression by altering transcription factor and epigenetic marks. Cascading regulation of signaling pathways and functional integrity therefore contributes to the pathogenesis of multiple diseases. Modulation of these signaling pathways is gaining momentum as a putative therapeutic strategy in cancer treatment strategies. This chapter aims to demonstrate the well-known molecular interrelationship principles between microRNAs and ROS generation in cancer pathogenesis. This chapter also summarizes the key characteristics and

S. Avvari Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad, India M. Rishitha · K. S. Manjari University College for Women, Koti, Osmania University, Hyderabad, India S. Poornima Department of Genetics and Molecular Medicine, Kamineni Life Sciences, Hyderabad, India I. A. Khan (*) Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Prasad, P. Santosh Sushma (eds.), Role of MicroRNAs in Cancers, https://doi.org/10.1007/978-981-16-9186-7_5

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molecular functional functions of known miRNAs related with ROS in malignancies. Keywords

MiRNA · Cancer · Oxidative stress · Reactive oxygen species · Signaling pathways

5.1

Modulation of Oxidative Stress by MiRNA in Cancer

Adenosine triphosphate (ATP) is created in the mitochondrial cell of eukaryotic cells during aerobic breath. As a result of this oxidative metabolism and other mobile reactions, various chemicals known as reactive oxygen species (ROS) are generated by cytokines, xenobiotics, and bacterial invasion. Most of these compounds are beneficial in a concentration of less than 5%. Low levels are essential for subcellular events like activation of enzymes, signal transduction, disulfide bond formation for protein folding, and activation of apoptotic mechanisms. An increase in these molecules can be toxic for the cell as they change the chemistry of almost the major molecules in the body, including DNA, RNA, lipids, and proteins (Farzaneh et al. 2018; Ray et al. 2012; Sosa et al. 2013; Veskoukis et al. 2012). The oxidative stress (OS) is the imbalance of the cell’s ability to detoxify the reactive intermediate by antioxidant response due to excess of ROS or oxidants. Biologically, a network of OS signaling pathways connected to cancer is implicated, as is interaction between the operating system and related genes. The functional players for genetic control, including microRNAs (miRNAs), have recently been shown to be implicated in the cancer-associated OS signaling pathways. This view shows that OS signal regulates the expression of miRNAs that can function in OS tumors as imperative players. Documented study suggests that the OS signals are connected to the miRNA regulation mechanisms in the development and progression of cancer (Akbari et al. 2020). The purpose of this chapter is to explain the role of miRNA, oxidative stress, and cancer. The four types of reactive species created by a reactive nitrogen species are (1) ROS, (2) reactive chlorine species (RCS), (3) reactive nitrogen species (RNS), and (4) reactive sulfur species (Korbut et al. 2020). ROS include superoxide anion (O2), hydrogen peroxide (H2O2), hydroxyl radical (OH), singlet oxygen, and ozone (Phaniendra et al. 2015). RCS consists of chlorine-containing compounds, like HOCl and chloramines, which are capable of chlorinating and oxidizing other molecules (Gray et al. 2013). Reactive sulfur includes free hydrogen sulfides, acidlabile sulfides, and bound sulfane sulfur (Kolluru et al. 2020). RNS consists of nitric oxide, nitroxyl anion, nitrosyl cation, nitrous acid cation, nitrosonium cation, higher nitrogen oxides, S-nitrosothiols, and dinitrogen trioxide (Pizzorno and Murray 1999). Both the ROS and RNS are abundantly produced during intracellular metabolic processes such as electron transport systems, where they interact to generate even more free radicals. The half-lives of the reactive species depend on the

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molecular stability and vary from nanoseconds to hours. Depending on the sources, OS can be either internal or external. Electrons are usually transported by the mitochondrial transport chain to water to reduce O2, but around 1–3% of the electrons escape from this system and form superoxide. Other internal ROS sources include phagocyte oxidative burst during killings of bacteria and viruses and the derived foreign proteins, peroxisome metabolism, the metabolism of xanthine oxidoreductase, and arachidonate pathways (Birben et al. 2012; Sharifi-Rad et al. 2020). Redox signaling pathways, such as nuclear erythroid factor (Nrf2)/Kelch-like ECH-associated protein1 (Keap1), superoxide dismutases (SOD)/catalase (CAT), mitochondrial pathway, and other important enzymes, together with microRNAs may modulate intracellular redox hemostasis and influence carcinogenic processes.

5.2

Nrf2/Keap1 Signaling Pathway

Both Nrf2 and Keap1 have been identified as critical regulators of the bodies response to OS (Wu et al. 2019a; Taguchi and Yamamoto 2017). Nrf2/Keap1 complexes disintegrate in the presence of OS, and Nrf2 is transported to the nucleus. This change increases the expression and activity of numerous antioxidant genes, which suppress cell apoptosis, while also promoting cancer cell survival and carcinogenesis (Itoh et al. 2010; Ayers et al. 2015). Earlier findings showed that several microRNAs, such as miR-144, miR-28, miR-200a, and miR-93, target the Nrf2 signaling pathways. Karihtala et al. (2019) discovered that miR-93 overexpression in pancreatic cancer was negatively associated with Nrf2 and predicted higher cellular differentiation. Singh et al. (2013a) studies discovered that in cases of breast cancer, miR-93 could reduce the number of Nrf2-dependent carcinogenic pathways. Silencing miR-93 could induce apoptosis and hinder the formation of colonies, mammals, and cell migration. miR-200a is another microRNA that targets the Nrf2/Keap1 pathway. Eades et al. (2011) and Yang et al. (2011) revealed that miR-200a and miR-28 may affect the Nrf2 expression in the cells of breast cancer via targeting Keap1 mRNA directly. Gu et al. (2017) have discovered that miR-155 uprisings can encourage tumor cell colony formation and migration and suppress cell death in lung cancer cells. This was achieved by the upgrading of the signal pathway Nrf2/Keap1. The cellular levels of NrF2, NAD(P)H quinone oxidoreductase 1, and heme oxygenase-1 (HO-1) were reduced and will drastically lower miR-1, restrict the survival and immigration of cancer cells, and facilitate cell apoptosis. MicroRNA regulator miR-125b is also critical for Nrf2. miR-125b was described as the upregulator of peroximic 2A, a molecule antioxidant protective of cells from oxidative damage (PRXL 2A) (Chen et al. 2019). Later, Nrf2 was discovered to be a downstream miR-125b-PRXL2A axis effector.

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Signaling Pathway in Mitochondria

Mitochondria are regarded to be one of the primary ROS emitters (Sabharwal and Schumacker 2014; Han et al. 2019). In order to sustain proper cellular activities, mitochondria constantly fission and fusion and produce a suitable level of ROS in reaction to changes in the surrounding environment. OS can result in aberrant mitochondrial and associated signal pathway malfunctioning (Han et al. 2019). The activities and expressions of various mitochondrial proteins involved in redox homeostasis retention could be regulated by the microRNAs. It has been discovered, for example, that increased miR-210 can boost ROS levels via inhibiting the recruitment of iron-sulfur cluster proteins in cancer cells ISCU1/2. Mitochondrial miR-210 malfunction would update the pace of glycolyze and increase the susceptibility of tumor cells to glycolysis inhibitors. The overexpression of miR-210 may also induce hypoxia ROS production indicating a worse colorectal cancer prognosis (Chen et al. 2010; Chan et al. 2009). Tag Scherer and colleagues found that miR-210 might trigger death of cancer cells by the production of ROS. The miR-34a was discovered to limit ROS generation by downregulating the genes that code for ROS and mitochondrial chemicals that lead to apoptosis resistance. The reactivation of miR-34a may alert tumor cells to oxidative stress (Lei et al. 2016). According to Muys et al. (2019), miR-450a can shrink tumors by reducing glycolysis and glutaminolysis and targeting a group of related mitochondrial genes such as argonaute 2 (AGO2), TIMMDC1, ATP5B, and MT-ND2. miR-450a overexpression reduced mitochondrial membrane potential but enhanced glycolysis absorption and survival with less invasive types of cancer cells (Orang et al. 2019). Kao et al. (2019) noted that miR-31 can target SIRT3 to eliminate mitochondrial activity and increase the stress of oxidation in oral cancer. A previous study by Fan et al. (2019) discovered a controlled chemoresistance of mitochondrial microRNAs (mitomiR) mitomiR-2392 in tongue squamous cell carcinoma via oxidative downregulation and upregulation. According to the findings of the Xu group (2018), miR-17-3p may decrease three major mitochondrial antioxidant enzymes manganese superoxide dismutase (Mn-SOD), glutathione peroxidase 2 (Gpx2), and thioredoxin reductase 2, as well as increase prostate cancer cell radiation sensitivity. These studies have a substantial impact on the regulatory role of microRNAs in protein synthesis and function.

5.4

Signaling Pathway of SOD/CAT

SODs include members of the Fe/Mn-SOD, Cu/Zn-SOD, and Ni-SOD families and are metal ion cofactor-requiring enzymes that catalyze the dismutation of O2
into O2 and H2O2. Unlike the Nrf2/Keap1 system, the SOD/CAT system performs antioxidant activities by encouraging particular metabolic reactions that eliminate accumulated ROS. Mn-SOD expression has been observed to be increased in gastric and esophageal squamous cell carcinomas (Bhattacharyya et al. 2014). Mn-SOD activity and expression are also linked to colorectal cancer. Cu/Zn-SOD, on the other

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hand, is reduced in cancer tissues when compared to normal tissues (Miranda et al. 2000). MicroRNAs can target most SODs in order to modulate their antioxidant activities. In several facts of carcinogenesis, miR-21 has proven to have a key function. miR-21 was shown to increase carcinogenesis by removing SOD2/SOD3 by targeting the TNF-α production, hence reducing the dismutation of superoxide to the less harmful H2O2 molecule (Jajoo et al. 2013). Wang et al. (2014a) found that miR-146a was capable of degenerating mRNA CAT. Silencing miR-146a has been shown to increase antioxidant capacity in lung cancer cells treated with cisplatin by boosting CAT levels, which was the primary cause of drug resistance. Patel and coworkers (2017) discovered that miR-155, released through exosomes, might enhance SOD2 and CAT levels by blocking a gemcitabine-metabolizing enzyme, DCK. In addition, it was explored that Mn-SOD-induced colorectal cancer metastasizing may be directed and downregulated directly by miR-212 (Meng et al. 2013). Outward OS causes include UV radiation, contaminants of the environment, smoking and alcohol, inappropriate use of medicines, and exercise. The tumor suppressor p53 can be caused by OS and radiation-induced damage. Then, p53 influences the expression of many miRNAs, the most important being miR-34a and miR-34b/c. Research has demonstrated that loss of miR-34 expression leads to apoptotic resistance caused by transcription factors encoded in p53 (Hermeking 2010). ROS can also change miRNA expression by epigenetic changes such as methylation or acetylation; such a change in miR-125b and miR-199a was identified for ovarian cancer (He and Jiang 2016). External stressful situations, like ionizing radiation and exposure to H2O2 or hypoxia, can change miRNA expression (Simone et al. 2009; Wang et al. 2010). The epidermal growth factor receptor (EGFR) oncogene, for example, can phosphorylate the AGO2 protein when activated by hypoxia, preventing it from interacting with DICER1 (Shen et al. 2013). Hypoxia may also inhibit the expression of DROSHA and DICER1 in cancer cells, leading to inadequate miRNA biogenesis (Rupaimoole et al. 2014).

5.5

ROS Controls MicroRNA Expression and Biogenesis

ROS influenced numerous elements of microRNA transcription, maturation, and function, according to the emerging evidence. The activities of essential proteins controlled in the production of microRNAs could directly be modulated by ROS. Some transcription factors were activated by OS, and the synthesis of a subset of microRNAs was directly stimulated. ROS was also implicated in the epigenetic alterations (DNA methylation changes and histones) that were controlled by particular transcripts of microRNA (Nallamshetty et al. 2013). In conjunction with those findings, ROS has been identified as a critical proximal regulator of the synthesis of microRNAs and the role to raise ROS levels by increased OS (Cross et al. 2015). The introduction of exogenous H2O2, for example, may lead to a redox-sensitive and functional expression for ROS-hemostasis (MiR-21), as well as the downregulation of miR-27 and miR-29b (He and Jiang 2016; Leisegang et al. 2018). In addition,

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pre-microRNA transcripts into mature microRNAs are also processed in ROS production. A crucial maturation regulator for canonical microRNAs is the RNA-binding DiGeorge critical region-8 (DGCR8). The removal of DGCR8 would cause all canonical microRNAs to fail (Guo and Wang 2019). Dicer is another pivotal protein for the formation of mature microRNA biogenesis engines, discovered as reduced by the modulation of the Nrf2/Keap1/ARE pathway by an OS (Ungvari et al. 2010, 2013). Increased Nrf2 activity may upgrade Dicer protein expression. The dicer gene’s 5-flanking region suggested that the Nrf2/ Keap1/ARE pathway is a significant regulator of microRNA synthesis. Cheng et al. (2013) demonstrated the existence of an ARE consensus sequence. In addition, during OS, the let-7 family of microRNA have been reported to exaggerate. Since the let-7 microRNAs might remove the Dicer genes directly, the decreased expression of Dicer and subsequent microRNA-related redox imbalances have been proposed as potential regulation mechanisms (Mori et al. 2012).

5.6

Transcription Factors

It is worth noting that the expression of microRNAs is controlled by a number of transcription factors, including nuclear factor B (NF-B), c-Myc, and HIF-1. Multiple studies have shown that some of these ROS-sensitive transcription factors indicate that aberrant microRNA expression in carcinogenesis is intimately linked to OS. Certain microRNAs, such miR-19a, miR-29, miR-31, or miR-155, which might be activated or disabled with ROS, were shown to be regulated through NF-B (Leisegang et al. 2018; Cheleschi et al. 2019). Production of TGFβ1-mediated ROS could enhance the translocation of NF-κB atom and, consequently, miR-146a and miR-21 in lung and colorectal development (Pogue et al. 2009). Instead, OS caused by TNF-α could decrease NF-κB activity and its target miR-19a and miR-155 (Kim et al. 2017a). In addition, miR-34a and miR-181a were discovered to mediate cell death and OS through NF-κB pathway (Cheleschi et al. 2019). These investigations have shown an extensive regulation mechanism for ROS-NF-κBmicroRNA. HIF-1α, a key ROS response factor, was discovered to be able to directly link the transcription of miR-210 to its promoter region which results in a diagnosis of cells (Wang et al. 2014b). Furthermore, a range of microRNAs such as miR-135, miR-421, milR-382, and miR-687 have also been discovered to be regulated by HIF-1α, which were abnormally elevated during tumor growth and metastasis (Seok et al. 2014). Furthermore, c-Myc, which is likewise ROS-sensitive, could either up-release the expression of oncogenic microRNA, such as miR-17, or inhibit the expression of some microRNAs of the tumor suppressor, such as miR-34a, miR-137, and miR-15a (Dang 2012). c-Myc-miR-137-EZH2 pathway regulatory status for ovarian cancer has been observed by Sun and colleagues (2019). Activated c-Myc-miR-137-EZH2 axis was detected and sustained by high ROS generation in chemoresistant ovarian cancer cells. Li and colleagues (2014) investigated whether MYC could maintain a neoplastic state by suppressing a specific set of chromatin regulatory genes, such as Hbp1, Sin3b, and Btg1, as well

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as the apoptosis regulator gene Bim, and thus regulating cell survival, proliferation, and apoptosis, by regulating miR-17-92. The emerging notion of the regulatory network TF-ROS-microRNA presented important prospects for the complex function and regulation of microRNA during carcinogenesis.

5.7

Epigenetic Changes

Epigenetic changes are another essential regulatory mechanism that should be highlighted. Either DNA methylation or histone alterations are certainly intimately associated with diverse environmental conditions, especially oxidative stresses. Two significant categories of enzymes are DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) that play a fundamental role in gene transcription’s epigenetic control, including microRNAs. The expressions of DNMT and HDAC may be controlled by OS and thus constitute a key control mechanism that allows ROS to affect the expression and biogenesis of microRNA. For instance, HDAC4 could be overexpressed to miR-1 and miR-206 promoter deacetylation and reduce gene expression in cancer cells under oxidative stress that led to advancement of lung cancer (Singh et al. 2013b). Apoptosis in lung cancer cells could be caused in SAHA, a histone deacetylase inducer via miR-129-5p upregulation (You and Park 2017). Zhang and colleagues (2012) have detected miR-29 epigenetic regulations by targeting lymphoma HDAC3, MYC, and EZH2. The study was concluded as MYC removed miR-29 by generating an HDAC3 and EZH2 corepressor complex. MYC helps to upregulate the EZH2 by blocking miR-26a. By downregulation of miR-494, EZH2 may, on the other hand, cause MYC expression, which would produce positive feedback. Collaboratively, the suppression of HDAC3 and EZH2 inhibits the MYC-EZH2-miR-29 axis, therefore reducing miR-29 targeted genes and decreasing the development of lymphoma.

5.8

Cancer Antioxidant Mechanisms and MicroRNAs Related to ROS

Reactive species are scavenged by the natural system antioxidant. There are numerous forms of endogenous antioxidants, natural antioxidants, and synthetic antioxidants. Glutathione, coenzyme Q, alpha-lipoic acid, ferritin, bilirubin, uric acid, metallothionine, melatonin, l-carnitine, SOD enzyme, glutathione peroxidases, thioredoxins, CAT, and peroxiredoxins are the endogenous antioxidants (PRXs). Carotene (vitamin A), tocopherol (vitamin E), ascorbic acid (vitamin C), glutathione, lipoic acid, and polyphenol metabolites are additional natural antioxidants derived from the diet. N-acetyl cysteine, pyruvate, butylated hydroxytoluene, propyl gallate, butylates, and selenium are included in the synthetic antioxidants (Yoshida et al. 2003). Specific miRNAs are shown to protect the compounds against oxidative damage. The natural polyphenol component ellagic acid, for example, found in many plant extracts and fruits can play a role in a wide range of antifungal actions,

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antioxidants, and antidiabetes (Uzar et al. 2012). This substance controls OS damage in the model of diabetes mellitus by raising miR-223 expression and targeted the Keap1-Nrf2 route (Yang et al. 2014). The reduction in miR-223 expression owing to dramatically elevated glucose levels will increase the Keap1 protein expression level and then decrease superoxide dismutase and heme oxygenase 1 enzyme (HO-1), finally leading to OS (Ding et al. 2019). Treatment with this compound can thereby reduce OS and formation of ROS. Cancer cells increase antioxidant factors, such as HO-1, in oxidative conditions created by chemical therapy, and thereby boost the antiapoptotic characteristics to prevent OS caused by anticancer medicines (Sullivan and Graham 2008). Oxidative inputs coexist with endogenous antioxidants in a tight balance. OS is caused when the balance between prooxidant and antioxidant is lost (Veskoukis et al. 2012). These reactive substances cause DNA breakage and DNA repair system mistakes. DNA oxidation causes DNA mutations and causes carcinogenesis in those reactive species (Matsui et al. 2000). Polyunsaturated lipids integrated into the cell membrane are sensitive to reactive species oxidation. Lipid peroxidation increases the permeability of the cell membrane and may cause apoptosis (Halliwell and Chirico 1993). OS changes the protein structure and loss of protein function of chemical groups such as aldehydes, ketones, and thiol (Levine 2002). OS is also promoting many elements of tumor growth, including (a) cell growth, (b) apoptosis avoidance, (c) invasion and metastasis of the tissue, and (d) angiogenesis. In relation to cellular proliferation, OS has an impact on various metabolic pathways involving essential protein signaling and mitogenic protein kinases (MAPK) (Matsuzawa and Ichijo 2008; Nguyen et al. 2009; Wiemer 2011). The main regulator of the antioxidant response is the major signaling proteins, such as the two-component Nrf2. P38α is an OS sensor and is necessary to control the development of tumors through its redox sensing function (Luo et al. 2011). As opposed to MAPKs, p38α reduces apoptosis or blocks the development of cancer. ROS also acts as a powerful mutagen that initiates cancer. The expression of oncogenes and suppressor genes can be altered by epigenetic alterations due to OS. The oncogenic mutation, instead, can increase the generation of ROS.

5.9

MiRNAs in Cellular Growth Under Oxidative Stress

OS alters the action or expression of the miRNA enzymes. One of the experiments using murine macrophage cells (RAW 267.7) used H2O2 to evaluate the profile of miRNAs responding to OS. Another study discovered a number of miRNAs that respond to stress, including miR-27a*, miR-29b*, miR-242*, miR-27b*, and miR-21*, all of which, with the exception of miR-21*, showed a drop in expression (Thulasingam et al. 2011). Alternative study found that miR-21 interacts with programmed death factors to protect myocytes against H2O2-induced damage and apoptosis in vascular smooth muscle cells. As a result, it is argued that miRNAs have the ability to control oxidative effects (Cheng et al. 2009). The downregulation in human bronchial epithelial cell line (16HBE) by miR-216a-5p owing to H2O2

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therapy leads to a lack of inhibition of high-mobility group protein expression box 1 (HMGB1). Increased expression of miR-216a-5p in the H2O2-induced cell by miRNA mimic can alter cell viability and apoptosis through HMGB1 targeting (Chaoyang et al. 2019). Furthermore, OS conditions promote miRNA expression as well. The ROS-induced NF-κB may enhance miRNAs, particularly miR-150-3p, in terms of expression. The miR-150-3p suppresses the osteogenic β-catenin mesenchymal stem cell differentiation (Wang et al. 2016). However, miR-424 expression reduces under OS and bone formation with mesenchymal stem cell development. miR-424 is inhibited under OS circumstances when the expression of FOXO1 is induced (Li et al. 2017). In metabolism, cell proliferation, resistance, and apoptosis, the FOJO family plays a leading role (Wang et al. 2014c). ROS and microRNAs were both identified to control growth and proliferation of cells. With miR-93, the Nrf2/Keap1 pathway was revealed to be critical regulators of endothelial glycolysis and cell proliferation and to regulate the effects of oxidized phospholipids on endothelial activation (Kuosmanen et al. 2018). KRAS activation may cause miR-155 increase in pancreatic cancer cells. Overexpression of miR-155, via suppressing FOXO3a, could reduce key antioxidants such as SOD2 and CAT and boost cell growth (Wang et al. 2015). He and Jiang (2016) discovered that miR-200a and miR-141 overexpression might influence ROS generation under oxidative stress by targeting p38a and increase cell growth and proliferation. Another example was miR-192-5p, which was found to be increased by H2O2 in a p53-dependent way. Downregulated miR-192-5p may have an impact on a variety of biological functions, including cell cycle, DNA repair, and stress response. As a result, miR-192-5p overexpression drastically reduced endothelial cell growth and cell death (Fuschi et al. 2017). Furthermore, Degli Esposti and colleagues discovered that miR-500a-5p can directly regulate a number of OS-related genes. H2O2 exposure increased miR-500a-5p expression, while decreasing transcription of OS-related genes NFE2L2 and TXNRD1. TXNRD1 overexpression has been linked to the prognosis of ER+ breast cancer. As a result, their research identified miR-500a-5p as an OS response microRNA whose expression may be linked to cancer progression and survival (Degli Esposti et al. 2017).

5.10

MiRNAs Under Oxidative Stress and Apoptosis Avoidance

CD274, commonly known as PDL1, is found on chromosome 9p24.2 and encodes a 290 amino acid transmembrane protein (Deng et al. 2014). Previous research has discovered that CD274 is highly expressed on the surface of many cancer cells, including bladder cancer (Amponsa et al. 2019), colorectal cancer (Wu et al. 2019b), lung cancer (Téglási et al. 2019), and so on, implying that CD274 plays a role in tumor growth. The hsa-miR-570-3p study by Wang et al. (2020) revealed inhibition of the proliferation, invasion, and migration of three negative cell breast cancer cells produced by apoptotic cell caused by targeting CD274. OS increases p38 c-Jundependent production of miRNA-570-3p. miR-570-3p is caused by OS through p38 MAPK-dependent AP-1-mediated transcription and causes senescence, whereas

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miR-0570–3p upregulation leads to cycle arrest, senescence-associated secretory cytokine, and elevated MMP production (Baker et al. 2019). Celled death, or apoptosis, is frequently characterized by several morphological traits and biochemical pathways that are dependent on energy. Apoptosis is thought to be a key aspect of many cell processes, including cell rotation, atrophy, and necroptosis (Ouyang et al. 2012; Elmore 2007). ROS plays a key part in the control of many cell death pathways, for example, RAS/MAPK and/or JNK pathways (Rezatabar et al. 2019; Lee et al. 2013). Wu et al. (2018) reported that the ginsenoside Rh4 (RH4), in which Rh4 is an anticancer indicator and has high potential, could cause cell death and autophagy by activating ROS/JNK/p53 pathway in colorectal cancer cells. Mohammad and his colleagues (2019) showed that JNK signaling could activate the Nrf2/Keap1 pathway, while simultaneously contributing to the death of piperlongumine-induced cells in cancer cells. In addition, Yan and colleagues (2019) observed that miR-762, through NADH dehydrogenase subunit 2, the regulation of cell apoptosis, was participating in the mitochondrial function. Furthermore, downregulation of miR-101-3p led to increased Bim expression which activated the apoptosis pathway through interaction with Bcl-2, reducing mitochondrial membrane potentials, ROS generation, and activation of the caspase (Kim et al. 2017b). Pant and colleagues (2017) have demonstrated that, while anaerobic fermentation of dietary fibers, butyrate, one of the short-chain fatties of the gut microbiota, could elicit ROS-mediated apoptosis through a miR-22/SIRT-1 regulation of the pathway in hepatocells. These investigations showed that microRNAs could govern programmed cell death or apoptosis by targeting several ROS-related pathways. Ferroptosis, an iron-dependent regulated form of necrosis, has recently been identified as an important regulatory mechanism of cell death caused by ROS buildup (Yang and Stockwell 2016). Their intricate cellular signaling management regulation in relation to cell death and apoptosis has led to great interest in iron and iron-mediated OS (Nakamura et al. 2019). miR-137 has demonstrated that ferroptosis is negative by directly targeting the SLC1A5 glutamine carrier in the melanoma (Luo et al. 2018). Xiao and colleagues (2019) noted a significant decrease in erastin-induced growth inhibition and endothelial cell production of ROS due to overexpression in miR-17-92. Further studies revealed a correlation between erastininduced ferroptosis and downregulation of GPX4 and overexpression of ACSL4. miR-17-92 could target directly the A20-ACSL4 axis and so prevent ferroptosis to endothelial cells. Zhang and colleagues (2018) have also reported upregulating miR-9 by directly linking to its 3-UTR, which then reduces erastin- and RSL3induced ferroptosis, inhibiting glutamic-oxaloacetic transaminase GOT1.

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Epithelial-Mesenchymal Transition and Tumor Invasion and Metastasis

In a plethora of pathological circumstances, including organ fibrosis and cancer invasion and metastasis, the epithelial-mesenchymal transition (EMT), a process in which epithelial cells acquire mesenchymal properties, has been recognized (Nieto et al. 2016; Pastushenko and Blanpain 2019). The EMT process involves ROS and microRNA dysregulation, which affects the invasion and metastasis of the tumor. Several microRNAs can directly affect the EMT process in normal cells or tumor cells (e.g., miR-200 families). The miR-200 (miR-200a, miR-200b, miR-200c) and miR-205 families were evidently decreased in cells which received EMT following treatment with TGFβ. Further investigations have shown that these microRNAs can manage the expression of E-cadherin via SIP1 and ZEB1 targeting. Breast and prostate cancer cells were sufficiently inhibited to trigger EMT processes (Kong et al. 2008, 2009). Xiao and colleagues (2015) have discovered that H2O2 treatment might substantially increase the expression of miR-200 family. The increase of miR-200-3p regulated the oxidative tension response mediated by H2O2 by targeting p38a. De Chen and colleagues (2015) discovered that targeting miR-373 may aid the process of epithelial-mesenchymal transition (EMT) and cancer metastasis in breast cancer by reducing the expression of thioredoxin-interacting protein (TXNIP). Using the HIF-1α-TWIST axis as an example, miR-373 stimulated the TXNIP signaling pathway mechanistically. By binding to the promoter of the miR-371-373 cluster, TWIST could stimulate the production of miR-373. In a study they carried out, they found that miR-373 could lead to tumor cell EMT and metastasis via encouraging metastasis-promoting factors including miR-373-TXNIP-HIF-1α-TWIST signaling axis in breast cancer. Even with that in mind, Martello and colleagues found a particular family of microRNAs known as miR-103/107, which suppressed microRNA production by interfering with Dicer and was highly associated with breast cancer metastasis. The terms “migratory capacity” and “migratory power” imply that miR-103/107 promotes migratory processes and facilitates metastasis via controlling the EMT process. Rising levels of the miR-103/107 family may limit the mobility and spread of cancer cells. Tumor invasion and metastasis were shown to be dependent on the ROS-microRNA network. The identification of signaling pathways that link OS to cancer and so aid in the development of improved cancer therapies is one possible result of such studies (Martello et al. 2010).

5.12

Role of Oxidative Stress and MiRNA in Cancer

Cancer cells are thought to be descended from a small subset of tumor cells with a strong capacity for self-renewal and differentiation, known as cancer stem cells (CSCs) or tumor-initiating cells. More and more data show that miRNAs act as CSC regulators and are connected with ROS production during tumor progression and development of cancer. Some miRNAs, such as let-7a, miR-34a, miR-21, miR-200, and miR-210, could be implicated in ROS generation modulation for

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CSCs (Lin 2019). In a previous study, let-7 works as a negative CSC-mediated regulation regulator for prostate and pancreatic cancer by targeting PTEN and LIN28b. Recently, OS has reduced p53-dependent let-7 expression in several cancer cells. Some experimental studies have shown that in CSC subpopulations, the expression of miR-21 is significantly elevated in comparison with that in non-CSC hypobromite in vitro and in vivo. In particular, cell migration, invasion, and EMT in breast cancer CSCs are reduced by miR-21. Another interesting finding is that OS induction of miR-21 expression, as well as cell migration and self-renewal, was found in CSCs from prostate and pancreatic tissue. Is another study, miR-21 activates the MAPK pathway and decreases SOD2, SOD3, and SPRY-2 expression via promoting the formation of ROS (Mei et al. 2013). CSC-related genes, such as CD44, and EMT markers are among the other studies that demonstrate miR-34a’s inhibitory effects on cell metastasis, cell migration, and self-renewal capacity. Researchers have found that the relationship between ROS and miR-34 has been observed. Stromal and tumor cells upregulate miR-34 expression in response to OS. The first research indicating that miR-200 is involved in stem cell differentiation appeared in 2009 (Peter 2009). CSCs and normal mammary stem/progenitor cells from both humans and mice all have reduced expression of all five miR-200 family members. Mechanistically, miR-200 downregulates the expression of B-lymphoma Mo-MLV insertion region 1 homolog (Bmil-1), Notch1, and Suz12, as well as suppressing the CSC self-renewal potential, recognized regulators of CSC and EMT biomarkers (Yu et al. 2014). Compared with MCF-7 parental cells, expression of miR-210 is elevated in MCF-7 spheroid cells and CD44+/CD24
MCF7 cells (Tang et al. 2018). In vitro and in vivo overexpression of miR-210 results in proliferation, self-renewal capacity, migration, and invasion, all of which are significantly inhibited by E-cadherin. Based on these findings, it can be concluded that the miRNA/ROS axis is crucial in a number of cellular activities associated with CSCs.

5.13

Conclusion

In total, several investigations were carried out to unravel the molecular mechanisms that underlie the ROS/miRNA axis and its role in carcinogenesis. The overlap of features of ROS and miRNAs in carcinogenesis is indeed present. ROS modulates miRNA expression as upstream regulators via transcriptional, posttranscriptional, and epigenetic control. MiRNAs, on the other hand, inhibit ROS synthesis (as a downstream mediator) and participate in ROS-mediated activities. MiRNAs and ROS can work together or against each other to control cancer growth. Many intricacies of their relationship, however, remain unknown and must be researched further. MiRNAs/ROS-mediated phenotypes are determined by the overall outcome of the downstream molecules and various signaling pathways in the specific setting. Treatment is still limited by ROS’ dual involvement in the progression of cancer. The functional roles of miRNA are different in cells that are cell-oriented to ROS, as explained in this chapter. Since these findings point to the potential application of certain miRNAs in various settings, this research opens the door to perhaps using

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these molecules as therapeutics. Another advantage of employing miRNA-target treatment is that it can target multiple genes in established pathways, while preserving miRNA across species with known sequences. It is important to note that various miRNA-based medicines are in development. A great illustration of this concept is the anti-miR-122 LNA-modified drug in clinical development (Lindow and Kauppinen 2012). New techniques to fight cancer are created because of the relationship between ROS-mediated activity and miRNA control.

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You BR, Park WH (2017) Suberoylanilide hydroxamic acid induces thioredoxin1-mediated apoptosis in lung cancer cells via up-regulation of miR-129-5p. Mol Carcinog 56(12):2566–2577 Yu G, Yao W, Xiao W, Li H, Xu H, Lang B (2014) MicroRNA-34a functions as an anti-metastatic microRNA and suppresses angiogenesis in bladder cancer by directly targeting CD44. J Exp Clin Cancer Res 33(1):1–13 Zhang X, Zhao X, Fiskus W, Lin J, Lwin T, Rao R, Zhang Y, Chan JC, Fu K, Marquez VE (2012) Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-cell lymphomas. Cancer Cell 22(4):506–523 Zhang K, Wu L, Zhang P, Luo M, Du J, Gao T, O’Connell D, Wang G, Wang H, Yang Y (2018) miR-9 regulates ferroptosis by targeting glutamic-oxaloacetic transaminase GOT1 in melanoma. Mol Carcinog 57(11):1566–1576

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MicroRNAs Targeting Tumor Microenvironment and Immune Modulation Sitara Roy and DKV Prasad

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs (~22 nucleotides) that regulate transcriptional and translational processes. In particular, miRNAs act as a link between immune response and tumor development by regulating the activation and recruitment of immune cells in the tumor microenvironment, resulting in immune modulation through the secretion of immune stimulating or immunosuppressive factors and thus contributing to oncogenesis. MiRNA immune gene therapy has the potential to revolutionize cancer treatment since it allows for cell treatment and reintroduction into the patient, while also providing higher safety margins than other conventional therapies. Keywords

MicroRNAs · Cancer · Immune system · Immune-related microRNAs · Innate immunity · Adaptive immunity · Tumor microenvironment · Exosomal miRNA · Immune checkpoints · Immunotherapy

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Introduction

The immune system, which consists of innate and adaptive responses, has evolved to preserve self-tolerance and identify foreign pathogens effectively. The innate immune system serves as the first line of defense against infections, and the adaptive S. Roy (*) University of California, San Diego, CA, USA D. Prasad Department of Biochemistry, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Prasad, P. Santosh Sushma (eds.), Role of MicroRNAs in Cancers, https://doi.org/10.1007/978-981-16-9186-7_6

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immune system is activated when the innate response is propagated. Adaptive immunity is mainly composed of T cells, B cells, and NK cells. It is a persistent, second-line defense against pathogenic attacks on the host, with memory cells that react to pathogens when encountered again. Both the immune responses are tightly regulated, and new studies show that microRNAs (miRNAs) play an important role in this complex system (Schickel et al. 2008; Gramantieri et al. 2021; Lindsay 2008). Since the discovery of the first miRNA, lin-4, in Caenorhabditis elegans in 1993, miRNAs have been demonstrated to influence a variety of biological processes in both healthy and pathological circumstances, including cell development, division, proliferation, and differentiation (Bhaskaran and Mohan 2014). Many studies have found that miRNA expression in various cancers is dynamically controlled. Considering the key role of the host immune response in shaping the tumor microenvironment, the role of miRNA-mediated communication between tumors and the immune system including exosomal miRNA, immunometabolites, and checkpoint regulators has also begun to be recognized. MiRNA expression can be dysregulated in cancer due to mutations in the miRNA biogenesis machinery, changes in the epigenetic regulation of miRNA-transcribing genes, and differential expression of transcription factors involved in promoting or inhibiting miRNA expression (Peng and Croce 2016; zur Hausen 2008). Proliferative signaling, invasion and migration, and apoptosis resistance are all caused by overexpression of tumor-suppressive miRNAs. On the other hand, loss of expression of miRNAs that target oncogenes produces comparable carcinogenic implications (Ding et al. 2019). Cancer cells are malignantly altered cells that vary from normal cells in appearance, genetic makeup, transcriptome profile, and protein presented on the cell surface, allowing the immune system to identify them as foreign entities (Fig. 6.1a). They can trigger the immune system by expressing tumor-associated antigens, germline antigens, and mutationderived neoantigens, resulting in severe immunogenicity. However, they have the ability to turn off the production of surface antigens, preventing differentiated T lymphocytes from recognizing them and allowing them to escape elimination (Waldman et al. 2020; Qin et al. 2019). The interaction of cancer cells with the immune system is a very dynamic and complex process involving the process of elimination of cancer cells as well as the escape of cancer cells from the immune response. Cancer may also control the immune system to meet its needs, whether by generating inflammation and causing genotoxic harm or by avoiding destruction by employing immunosuppressive regulatory cells and chemicals. Furthermore, cancer cells promote the production of negative chemicals such as programmed cell death protein1 ligand (PD-L1), which inhibits cytotoxic T-cell activity and therefore avoids the host immune system’s attack (Burnet 1970; Hodi et al. 2010; Dong et al. 2017). MiRNAs play a critical role in task execution in the tumor microenvironment, and exosomal vesicles aid communication between cancer cells and stromal cells (Santos and Almeida 2020; Tan et al. 2020). As a result, tumors can use differentially expressed miRNAs to interact with and disable the body’s defenses. Immune cells, on the other hand, can inhibit carcinogenesis by changing the expression of miRNAs in tumors (Fig 6.1b). In this chapter, we will highlight the role of miRNAs in the tumor microenvironment and immune modulation.

Fig. 6.1 MiRNA regulation of tumor progress by modulating immune responses in the tumor microenvironment. (a) miRNA role in tumorigenesis. (b) Tumor microenvironment

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MiRNA Dysregulation in Cancer

It is well established that miRNAs have a role in the genesis and progression of cancer. MiRNAs help maintain optimal cellular homeostasis in normal tissue by regulating gene expression (Lin and Gregory 2015). However, miRNAs have been shown to be significantly dysregulated in the majority of tumors. MiRNA profiling and deep sequencing studies show evidence of aberrant miRNA expression during tumorigenesis, metastasis, and angiogenesis of cancer (Iorio and Croce 2012). MiRNAs have also been shown to play an important part in the regulation of cancer stem cells, and they may act as an oncogene or tumor suppressors. Dysregulated cell growth, cell motility in carcinogenesis, and changes in hormonal stress response are some of the implications of altered miRNA expression that contribute to cancer progression. Experimental research on the miRNomes of cancer has demonstrated that the modulation of the altered miRNAs in cancer cells using anti-miRNA technologies or RNA replacement can restore miRNA functions and repair the signaling pathways and gene regulatory network, reversing the cancerous phenotype (Garzon et al. 2010; Loh et al. 2019). Several animal studies suggest that miRNA therapy could become the next alternative cancer treatment. In the future, developing compounds that interfere with miRNAs might be of significant pharmacological relevance. Remarkably, certain miRNA can genetically manipulate cancer cells into a pluripotent embryonic stem cell-like state, from which tissue-specific mature cell types can be generated.

6.3

Role of Exosomal MiRNA Derived from Tumors to Regulate Tumor Microenvironment

Exosomes are extracellular vesicles that are secreted by both healthy and tumorous cells which contain proteins, lipids, DNA, and RNA. Cross talk between cancer cells and cells in the tumor microenvironment, such as immune cells, fibroblasts, and many others, is mediated by exosomes and has been linked to carcinogenesis (Whiteside 2016). Exosomes are therefore used as a method of transport for tumor cells to deliver immunosuppressive miRNAs to immune cell subsets. Intercellular communication might be enabled by these circulating miRNAs (Salido-Guadarrama et al. 2014). These miRNAs are protected by RNA-binding proteins or packed in membrane-encapsulated vesicles the exosomes. According to current research, miRNAs identified in human melanoma exosomes control the tumor immune response. CD8+ T cells, unlike many other immune cells, do not internalize vesicles, but they do ingest exosomes from diverse tumor types (Xie et al. 2019). Latest research investigated the role of melanoma-derived exosomes in CD8+ T cells and discovered that they suppress T-cell responses by reducing TCR signaling and reducing cytokine and granzyme B production results in reduced cell’s cytotoxic activity (Seo et al. 2018). The TCR signaling and TNF production are controlled by miRNAs found in abundance in the exosomes, such as Homo sapiens (hsa)-miR3187-3p, hsa-miR-498, hsa-miR-122, hsa-miR-149, and hsa-miR-181a/b (Vignard

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et al. 2020). These melanoma-derived exosomes bind directly to TNF’s 30 UTR and inhibited TNF production in CD8 T cells. In addition, miR-3187-3p was found to specifically target PTPRC, a gene that encodes CD45, a critical modulator of T-cell receptor activation (Peinado et al. 2012). Research findings show that miRNAs in exosomes generated from cancer cells help in immune evasion and might be an important therapeutic target (Ingenito et al. 2019). In addition to their direct effect on T cells, tumor-derived exosomal miRNAs may influence T-cell responses indirectly by targeting other immune cell subsets in the tumor microenvironment. The miR-23a-3p, which is produced by endoplasmic reticulum-stressed hepatocellular carcinoma (HCC) cells, has been shown to impair T-cell activity in HCC tissues by targeting PTEN in macrophages. Decreased PTEN expression resulted in an increase in phosphorylated AKT, which is followed by an increase in synthesis of PD-L1 (Liu et al. 2019). MiRNAs from tumor-associated macrophage (TAM)-secreted exosomes, like tumor-derived exosomal miRNAs, also promote tumor growth and inhibit antitumor immunity (Chen et al. 2020). Two miRNAs found in TAM-derived exosomes, miR-29a-3p and miR-21-5p, have been shown to target the 30 UTR of STAT3, which is important for CD4 T-cell development into Th17 cells, resulting in a greater regulatory T (Treg)/Th17 cell ratio (Zhou et al. 2018). While tumor- or TAM-derived exosomal miRNAs can inhibit antitumor responses in the host, immune cells can also release miRNA-containing exosomes to combat cancer. Through the release of cytotoxic extracellular vesicles, healthy, activated CD8 T lymphocytes can deplete mesenchymal stem cells (MSCs) and limit tumor invasion and metastasis in vivo. The extracellular vesicles’ cytotoxic impact was linked to miR-298-5p, a miRNA that was able to cause apoptosis in MSCs by activating caspase-3. Research not only showed a unique effector method through which CD8 T lymphocytes regulate tumor growth, independent of their traditional direct cytotoxicity against tumor cells, but also indicates an antitumor impact of immune cellgenerated exosomal miRNAs (Hu et al. 2019).

6.4

Role of MiRNAs in Immune Regulation

The involvement of miRNA in regulating immunological responses such as growth, development, differentiation, stimulation, functioning, and aging of different immune cells has been increasingly recognized. Several miRNAs have been found to have very specialized expression patterns in organs associated with the immune system. Conditional knockout of Dicer (RNase III enzyme) of the miRNA biogenesis in early-stage thymocytes causes a substantial decrease in the survival of alphabeta lineage cells (Yang and Lai 2011; Cobb et al. 2005). The expression profile of several miRNAs influences the differentiation of hematopoietic progenitor cells into lymphoid or myeloid lineages (Cobb et al. 2005; Chung et al. 2011). This strongly implies that miRNAs play an important role in immune cell formation and function. Transcriptome analysis of CD4+ T cells with deficient bic/miR-155 indicated several genes regulated by miR-155 like cytokines, chemokines, and transcription factors, suggesting miR-155 plays a key role in the function of B and T lymphocytes and

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dendritic cells. miR-181 plays a crucial role in the hematopoietic B- and T-cell lineage differentiation (Zheng et al. 2018; Seddiki et al. 2014). The miR-17-92 cluster has recently been identified as a key participant in the development of the immune system, the heart, the lungs, and oncogenic events, according to a new study (Kuo et al. 2019; Mogilyansky and Rigoutsos 2013). miR-146 and miR-125 control the inflammatory responses and the outcomes of pathogenic infections by modulating innate immune signaling (Lee et al. 2016). Dysregulation of miR-155 leads to the development of autoimmunity, chronic inflammation, and cancer (Pashangzadeh et al. 2021). Endogenous damage-associated molecular pattern molecules (DAMPs) produced by injured or stressed cells associated with an inflammatory response substantially increased miR-34c and miR-214 in human peripheral blood mononuclear cells (Unlu et al. 2012). Intercellular cell adhesion molecule expression on tumor cells is suppressed by miR-222 and miR-339, reducing tumor cell sensitivity to cytotoxic T-lymphocyte-mediated cytolysis (Ueda et al. 2009; Fares et al. 2020). These findings support the view that miRNAs influence the outcome of various diseases by regulating both innate and adaptive immune responses. Hence, it is critical to comprehend how miRNAs modulate different physiological processes of the immune system in normal and diseased conditions.

6.5

MiRNAs Modulate Immune Responses in the Tumor Microenvironment

The tumor microenvironment is comprised of proliferating tumor cells, stromal cells such as cancer-associated fibroblasts, blood vessels, pericytes, endothelial cells, tumor-associated macrophages, and infiltrating inflammatory cells. The predominant inflammatory cells entering the tumor microenvironment are macrophages, T cells, and natural killer cells. Activated macrophages in the tumor microenvironment often existed in two phases M1 (classical-activated macrophages) and M2 (alternativeactivated macrophages) phenotype. Pathogens and tumors are attacked by M1 macrophages, but M2 macrophages have an immunosuppressive nature (Lin et al. 2019; Hallam et al. 2009). According to research, miRNAs play a major role in the biological process of macrophage polarization conversion between M1 (antitumorigenesis) and M2 (pro-tumorigenesis). Myeloid-derived suppressor cells (MDSC) reduce the antitumor activities of CD4+ and CD8+ T cells and inhibit the activities of NK cells, adversely regulating immune responses (Bruno et al. 2019). Overexpression of miR-155 and miR-21 activated the STAT3 signaling pathway, resulting in a higher frequency of cytokine-induced MDSC and tumorigenesis (Li et al. 2014). Upregulation of miR-30b/30d is linked to an increase in T regulatory cell (Treg) recruitment in tumors, as well as metastatic spread, quicker recurrence, and shortened survival (Facciabene et al. 2012; Chaudhary and Elkord 2016). Downregulation of miR-15 and miR-16 in cancer-associated fibroblasts on the stromal and tumor cells, promoting tumor development and progression, as well as cancer cell survival, proliferation, and migration (Musumeci et al. 2011). miR-135b promoted the oncogenic activities of nucleophosmin-anaplastic lymphoma kinase

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(NPM-ALK) by suppressing T-helper cell master regulators STAT6 and GATA3 and expressing IL-17-induced immunophenotype in ALCL, promoting tumorigenesis (Matsuyama et al. 2011; Suzuki et al. 2015). The expression of two cytotoxic molecules like granzyme B and perforin 1 that are abundantly expressed in ALCLs was substantially reduced when miR-135b was silenced, suggesting that miR-135b has a wide range of impacts on tumor immunophenotyped (Akbari et al. 2015). High levels of circulating miRNA-363 have been detected in lymphocytic leukemia patients compared to healthy controls. CD4-T cells ingest tumor-derived extracellular vesicles with higher levels of miR-363 from tumor B cells in chronic lymphocytic leukemia (Palma et al. 2017; Wang et al. 2008). In the tumor microenvironment, these B cells have enhanced motility, immunological synapse signaling, and interaction with other tumor cells. The miR-424(322)/503 cluster acts as a tumor suppressor, and genetic mutations that inhibit its expression inversely increase the expression of PD-L1, PD-1, CD80, and CTLA-4 immune receptors, suppressing the adaptive arm of the immune system and leading to epithelial involution, tumorigenesis, and chemoresistance (Xu et al. 2016; Zhang et al. 2019). Different miRNAs have been found to have a role in regulating the development and functions of tumor-associated immune cells, particularly their capacity to influence T-cell signaling pathways, which could be highly scalable for cancer therapy (Xu et al. 2019; Cortez et al. 2019; Chen et al. 2021). MiRNAs in tumor cells transform the tumor microenvironment by non-cell-autonomous mechanisms, whereas miRNAs in adjacent cells preserve the characteristic features of the cancer (Conti et al. 2020; Rupaimoole et al. 2016; Si et al. 2019). Tumor angiogenesis, immunological infiltration, and tumor-stromal interactions are all influenced by miRNA regulation (Tan et al. 2020; Suzuki et al. 2015; Yang et al. 2018). Based on these findings, manipulation of single or many miRNAs has the potential to promote or inhibit certain immune subpopulations that support antitumor immune responses, thereby influencing carcinogenesis adversely.

6.6

MiRNAs Role in Metabolic Control of Immune Cells

Tumors can communicate directly with immune cells in the tumor microenvironment by producing immunomodulatory compounds. Increased expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the tumor microenvironment has been demonstrated to induce the development of numerous immunosuppressive cell types, including Treg cells, immunosuppressive dendritic cells, and macrophages, or to directly inhibit antitumor immunity (Meireson et al. 2020). Overexpression of IDO1 inhibited CD8 T-cell responses in colorectal cancer, resulting in increased tumor development. The ability of miR-448 to regulate gene expression has been demonstrated to improve CD8 T-cell survival by inhibiting IDO1 expression in colorectal cancer cells stimulated by inflammatory cytokine (IFN-γ) (Lou et al. 2019). Furthermore, when miR-153-mediated IDO1 suppression was combined with CAR T-cell treatment, in vitro T-cell killing capabilities were increased, and xenograft tumor development in mice was decreased (Huang et al. 2018a).

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Role of miRNAs in Regulating Immune Checkpoints

Immune checkpoint molecules are capable of regulating T-cell responses to selfproteins as well as tumor antigens by interacting with ligands. Multiple co-inhibitory receptors, including CLTA4, PD-1, and LAG-3, are upregulated when T cells are activated. Monoclonal antibodies targeting these immune checkpoints have shown tremendous clinical success in cancer immunotherapy in patients with a range of malignancies during the last decade (Pardoll 2012). Therapeutic blockage of the PD-1 pathway, in particular, has been hailed as one of the most significant advancements in cancer treatment. Not only was PD-L1, the ligand of PD-1, discovered to be upregulated in TAM as previously described, but it is also substantially expressed in a variety of tumors (Alsaab et al. 2017). PD-L1 expression may be controlled in a number of ways, and miRNA-mediated regulation of PD-L1 has lately gained prominence. Likewise, disruption of the PD-L1 30 UTR resulted in increased PD-L1 expression, indicating that miRNAs play a role in PD-L1 expression regulation (Qu et al. 2019). Multiple PD-L1 mRNA-miRNA interactions have been discovered in Epstein-Barr virus (EBV)-associated B-cell lymphomas, which are known to strongly rely on PD-L1 expression to escape immune responses (Anastasiadou et al. 2019). miR-34a suppression occurs when the viral protein EBNA2 and the B-cell-specific transcription factor EBF1 co-localize at the miR-34a promoter, which targets the PD-L1 lymphomas (Anastasiadou et al. 2019). Research studies also indicate that EBV-encoded miRNA also target PD-L1 and PD-L2 ligands. Both miR-34a and EBV miR-BHRF1-2-5p were shown to be associated with LMP1 expression, which is known to promote PD-L1/2 expression (Cristino et al. 2019). The efficient regulatory role of these counter-regulatory miRNAs makes them potential therapeutic targets. While miR-155 expression was similarly greater in the blood of EBV-positive patients, miR-155 binding to the PD-L1 30 UTR increased significantly PD-L1 expression, showing the complicated nature of miRNA-mediated gene regulation. CD47, which is widely expressed in blood cancers, sends signal to macrophages preventing them from eradicating tumor cells by phagocytosis that are also targets of miRNA. miR-708 binding to two locations in the CD47 30 UTR was shown to reduce CD47 levels in T-cell acute lymphoblastic leukemia cells (Nimmagadda 2020). In CCRF lymphoblastic cell lines, inducing miR-708 makes the cells more susceptible to phagocytosis, a result that was amplified by the addition of CD47 antibodies (Huang et al. 2018b). Furthermore, miR-155 has been reported to target CD47 in multiple myeloma patients. miR-155 was downregulated in advanced stages of the illness. When miR-155 was overexpressed in drug-resistant myeloma cell lines, it resulted in lower levels of CD47 and an increase in macrophage phagocytosis.

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Role of MiRNA in Tumor Progress in the Tumor Microenvironment

Tumor development is primarily dependent on the interaction of tumor cell and the microenvironment cells, as well as the regulation by the miRNAs. MiRNAs have a significant role in the complex interactions between tumor cells and stromal cells, such as cancer-associated fibroblasts, endothelial cells, and invading immune cells, during the tumor development. During the early stages of tumor development fibroblasts provide a stromal framework for the tumor cells (Bremnes et al. 2011). Upregulated miR-7 inhibits RAS-association domain family member 2 expression in fibroblasts present in the tumor microenvironment, which increases the proliferation of head and neck cancer. Loss of cancer-derived fibroblast-derived exosomal miR-3188 may influence tumor cell growth and fate (Yoshii et al. 2019). miR-211 generated from melanoma cells has been demonstrated to induce tumor fibroblast formation by directly targeting insulin-like growth factor 2 and activating mitogenactivated protein kinase signaling, which promotes melanoma development. M2 macrophage-derived exosomal miR-501-3p promotes tumor development in vivo via influencing the transforming growth factor signaling pathway (Su et al. 2021). In mice, macrophages transfected with a miR-125a mimic showed enhanced phagocytic activity and slowed the development of lung cancer (Zhong et al. 2017). Furthermore, higher levels of miR-27a blocked Th1 and Th17 cell differentiation mediated by dendritic cells, while promoting melanoma proliferation (Min et al. 2012). The downregulation of miR-638, which targets vascular endothelial growth factor, has been shown to enhance angiogenesis and liver carcinoma development, whereas its overexpression inhibits tumor angiogenesis (Cheng et al. 2016). miR-143/145 enhanced tumor development in lungs by targeting calcium/calmodulin-dependent protein kinase 1D, an inhibitory kinase whose overexpression inhibits endothelial cells from entering mitosis. Tumor microenvironment-associated miRNAs thus play a significant role in tumorigenesis. Tumor cells’ capacity to spread, which accounts for 90% of cancer deaths, is enhanced by interactions with tumor stromal cells, which are controlled by miRNAs. miR-126/miR-126* suppresses the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumor stroma in mouse xenograft model, reducing lung metastasis by downregulating stromal cell-derived factor-1 alpha and chemokine ligand 2 (Zhang et al. 2013). Tumor-released miR-9 may be transmitted to recipient normal fibroblast through exosomes, and miR-9 is secreted by fibroblasts to promote breast cancer cell motility by lowering E-cadherin levels (Baroni et al. 2016). Low levels of miR-200s in cancer-associated fibroblast have recently been discovered to enhance transcription factors Fli-1 and TCF12 expression and promote stromal extracellular matrix remodeling to induce tumor metastasis in breast cancer by upregulating fibronectin and lysyl oxidase (Tang et al. 2016). Interestingly, low-level cancer-associated fibroblast-derived exosomal miR-148b, which targets DNA-methyltransferase 1, an essential regulator of tumor metastasis, may be transmitted to endometrial cancer cells and promote endometrial cancer metastasis (Li et al. 2019). The production of miRNA-199a by mesenchymal stem

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cells has been demonstrated to improve the stem cell characteristics of breast cancer cells, increasing tumor initiation and spread (Cuiffo et al. 2014). Tumor-associated macrophages with abnormally expressed miRNAs also play a key role in tumor spread. miR-28-5p deficiency has been found to promote tumor metastasis by upregulating the production of IL34, which recruits these macrophages (Zhou et al. 2016). Exosomal miR-501-3p produced from M2 macrophages has been demonstrated to promote metastasis of pancreatic ductal adenocarcinoma in the liver and lungs (Yin et al. 2019). In conclusion, miRNAs in the tumor microenvironment have long been recognized as important modulator of tumor spread.

6.9

MiRNAs as Immunotherapy Target

Immunotherapies have emerged as one of the most promising treatment options for cancer therapy. MiRNAs are one of the most critical epigenetic factors involved in immune system modulation in the tumor microenvironment. An increasing amount of research studies suggests that cancer-derived immunomodulatory miRNAs might be promising targets for combating cancer immune evasion. The interaction of the programmed cell death-1 (PD-1) receptor and its ligand PD-L1 is a critical immunological checkpoint that cancer cells frequently use to avoid detection (Han et al. 2020; Akinleye and Rasool 2019). Cross talk with other immune targets or relevant signaling partners implicated in cancer progression regulates PD-1/PD-L1 signaling on several levels (Han et al. 2020; Perrichet et al. 2020). Immune checkpoint inhibitors improve the adaptive immune system’s ability to react to tumors. Different kinds of cancer have had therapeutic success inhibiting immunological checkpoint receptors including PD-1 and CTLA (Barrueto et al. 2020; Azoury et al. 2015; He and Xu 2020). Resistance to immunotherapy is caused in part by abnormal cellular signal transduction, and therefore combination therapy by co-inhibitory immune checkpoints can be beneficial. TIM-3 expression has been linked to PD-1 blockade resistance, and combination TIM-3 and PD-1 blockade has been shown to enhance responses in preclinical models (Sun et al. 2020; Oweida et al. 2018; Wolf et al. 2020). In addition to immune checkpoint blockade and immunosuppressive cytokine inactivation, treatment approaches aimed at increasing the activation of natural killer cells and macrophages, reversing the immune tolerogenic profile of the tumor microenvironment, and ablating immunosuppressive tumor-associated macrophages (TAMs) have been developed and tested (Navin et al. 2020; Guerra et al. 2020). Cancers have long been known to be poorly immunogenic, and enhanced suppression of immune checkpoints helps cancer cells to evade immune system recognition and clearance. Despite the success of the various immuno-cancer therapies in several patients, there are always subsets of patients who don’t respond to the treatment. Therefore, several modifications of cancer immunotherapy are implemented. MiRNA plays an important role in the evolution of the tumor microenvironment and the escape of tumor cells from the immune responses. Tumor escape from immune response may be classified into two groups depending on the cellular and molecular features of the tumor microenvironment. One major group shows a T-cell-

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inflamed phenotype comprising infiltrating T cells, a wide chemokine profile, and a type I interferon signature suggestive of innate immune activation (Corrales et al. 2017; Zhang and Zhang 2020). These cells appear to prevent immunological assault mainly through the dominant inhibitory effects of the immune system-suppressive pathways. The other group appears to prevent immune attacks through immunological exclusion or ignorance (Gajewski et al. 2013). The immunotherapeutic intervention of these two major groups of tumor microenvironment and on the specific miRNAs will result in maximal therapeutic benefit.

6.10

Conclusion

The role of miRNA in the tumor microenvironment in tumor progression and metastasis via regulating immune responses is described in this book chapter. Several miRNAs have been found to have deregulated expression in tumor cells and cells in the tumor microenvironment, emphasizing the importance of miRNAs in cancer initiation and progression. Several evidence of miRNAs regulating important elements of the tumor microenvironment involved in tumor angiogenesis, tumor cell proliferation, and metastasis are presented. Several mechanisms have been identified by which the miRNAs in the tumor microenvironment modulate the cancer development. MiRNA-related research offers a lot of promise for identifying key biomarkers and accelerating the development of new cancer therapies. Despite their tremendous promise in cancer diagnosis and anticancer clinical practice, microRNAs are not yet commonly used as cancer biomarkers and treatment targets in the clinical environment, due to a number of challenges that must be addressed before they can be widely used. Personalized regulation of the tumor microenvironment and the miRNAs to a condition favorable to antitumor immune responses will likely offer even more benefit to cancer patients receiving cancer therapies, based on the excellent clinical effectiveness shown with cancer immunotherapy.

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Role of Circulating MicroRNAs in Prognosis and Diagnosis of Cancers DKV Prasad, Vurla Prabhavathi, Pinninti Santosh Sushma, M. Sai Babu, P. Aruna, and Imran Ali Khan

Abstract

Cancer causes a spectrum of diseases based on the nature of the human disease. The early detection of cancer is still a clinical challenge, despite tremendous progress in the field of molecular oncology, documenting of molecular markers of specific tumors, and development of targeted therapies. Cancer studies have recently acquired relevance in understanding the function of the molecular basis of tumor growth, metastasis, and biomarkers for diagnosis, treatment response, and drug resistance. Liquid biopsies are still recognized as the gold standard procedure in cancer diagnosis because they provide more in-depth analysis than regular biopsies, which are both expensive and intrusive. The progression of D. Prasad Department of Biochemistry, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India V. Prabhavathi (*) Department of Obstetrics and Gynecology, NRI Institute of Medical Sciences, Visakhapatnam, Andhra Pradesh, India P. Santosh Sushma Biomedical Sciences Division, College of Community Health Sciences, University of Alabama, Tuscaloosa, AL, USA M. Sai Babu K-Genomics, Hyderabad, India P. Aruna Bronxcare Health System, Bronx, NY, USA e-mail: [email protected] I. A. Khan Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 D. Prasad, P. Santosh Sushma (eds.), Role of MicroRNAs in Cancers, https://doi.org/10.1007/978-981-16-9186-7_7

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multiple cancer diseases has been dramatically raised internationally, with the majority of the rising cases confirmed in the United States, followed by other countries of the planet. Novel cancer biomarker discovery is urgently needed for cancer diagnosis and prognosis. The consistent results of microRNAs (miRNAs) over the last decade have demonstrated to be an effective approach for various cancer detection and prognosis. The miRNAs are still considered to be potent gene regulators that influence mRNA stability and translation, while also being engaged in the transcription process. Deregulated miRNAs have been proven in studies to be appropriate potential biomarkers for cancer diagnosis and prognosis. MiRNAs act as phenotypic markers for many cancers, and they have the potential to be used as diagnostic, prognostic, and therapeutic tools. The circulating miRNA, on other hand, plays a significant role in tumor formation by regulating oncogenes and tumor suppressor genes that are underexpressed. The discovery of miRNAs has resulted in a paradigm shift in our understanding of gene expression, paving the way for development of novel diagnostic approaches as well as cancer treatment. It is well-known that extracurricular/circulating miRNAs can serve as biomarkers for various human diseases and also play an important role in intercellular communication. In this chapter, we discussed the relationship between miRNAs and ten distinct cancers, and additionally leukemias and multiple myeloma. The genetic contribution of miRNAs in each disease was identified, and we attempted to anticipate which circulating miRNAs indicators can be utilized to validate noninvasive biomarkers for human diseases. Finally, this chapter suggests that miRNAs can be used to screen specific cancers and forecast the prognosis of human cancer-related disorders, as well as confirm as a specific marker(s) depending on their ethnicities. Furthermore, cancer screening must be improved further until appropriate biomarkers are established for use in diagnoses and treatment of cancer patients. Keywords

Circulating miRNAs · Cancer · Prognosis · Diagnosis · MiRNA expression

7.1

Introduction

Cancer is documented as a cellular disease caused by uncontrolled tumor cell proliferation (Dong et al. 2018). Cancer generates malignant tumors as well as the loss of normal human organ function (Torpy et al. 2010). Cancer studies are currently focused on understanding the molecular basis of tumor growth, metastasis, and biomarkers for diagnosis, treatment approaches, and drug resistance. The development of liquid biopsies is regarded as a watershed moment in cancer research, and they are still regarded as the gold standard in cancer diagnoses since they provide more in-depth examination than traditional biopsies, which are costly and intrusive. Liquid biopsies are rapidly becoming more specific and standardized. DNA and proteins that are easily isolated from bodily fluids are indisputably excellent

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candidates for possible marker documents in liquid biopsy samples. Furthermore, circulating DNA and RNAs were provided as novel potential markers due to their sensitivity and specificity in detection, as well as being less expensive than conventional protein biomarkers. They can provide more dynamic perceptions of cell status than circulating DNA. The exploration of regulatory RNAs such as miRNA, circular RNAs (circRNAs), ribosomal RNAs (rRNA), transfer RNAs (tRNAs), Piwiinteracting RNAs (piRNAs), and long noncoding RNAs (lncRNAs) has increased our understanding of gene expression, disease, and therapeutic targets in a variety of human diseases. However, only a few RNAs, such as miRNAs and circRNAs, are stable in the majority of bodily fluids. Abnormal expression of circulating miRNAs in cancer could be of several reasons. Around 50% of coding genes of miRNA are located in the areas of genomic regions involved in cancers, which undergo translocation or amplification in malignancy. Another reason is the function variation of the enzymes involved in the biosynthesis of miRNA, like Drosha and Dicer1. Reduced levels of these enzymes have been reported in carcinoma of bladder and ovary, while raised levels are observed in gastric and cervical squamous cell neoplasms. The transcriptional errors of pri-miRNA could also cause alterations of circulating miRNAs in cancer (Tokarz and Blasiak 2012). Additionally, this book chapter will discuss various types of cancer and how the miRNA profiles could potentially lead to medical advancements relating to detection at early stage and a better understanding of these cancers.

7.2

MiRNAs in Solid Tumors as Diagnostic and Prognostic Markers

7.2.1

Breast Cancer

Breast cancer (BC), along with nonmelanoma skin cancer, is the most frequent cancerous growth in women worldwide (Waks and Winer 2019). Overall incidence rises fast during reproductive years and subsequently declines after menopause, when women are on average 48–50 years old (Key et al. 2001). CA15.3 and BR27.29 all are considered tumor markers in the diagnosis of BC. Because both of these are insensitive, the diagnosis is still based on histology tumor grading. As a result, novel biomarkers of higher quality are desirable (Chan et al. 2013). Oncogenic miRNAs such as 19a, 24, 155, and 181b were shown to be overexpressed in serum samples of BC patients at diagnosis, but decreased following surgical resection of the same patients (Sochor et al. 2014). Additionally, when compared to the lower-risk group, these miRNAs were considerably found in serum patients from the high-risk group. The relevance of miR-155 in distinguishing BC patients was proven, and distinct miR groups such as 10b, 34a, and 155 differentiated the metastatic stage of BC from control subjects. miR-34a levels were found to be aberrant in the early stages of tumor development (Roth et al. 2010). When assessing whole blood samples from preoperative stage and healthy controls, Heneghan et al. (2010) emphasized the importance of miR-155 in BC, prostate cancer, colon cancer,

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kidney cancer, or melanoma. In BC patients, there is a difference in the expression of oncomirs such as let-7a, miR-10b, and miR-155. Overexpression of miR-195, on the other hand, is thought to be distinctive to BC and may be able to distinguish BC from other neoplasms. Shimomura group previously investigated a combination of miRNA signatures including 1246, 1307-3p, 4634, 6861-5p, and 6875-59 that is capable of recognizing BC at an early stage with high sensitivity, specificity, and accuracy (Shimomura et al. 2016). The presence of a combination of miR-106b, vimentin, and E-cadherin is required for complete survival, and in terms of treatment response, high levels of miRs 200a and 210 in BC subjects with metastases were related with resistance to chemotherapy (Shao et al. 2019).

7.2.2

Colorectal Cancer

Colorectal cancer (CRC) is the second common most cause of death in both the genders globally. The morbidity and mortality of CRC can be mitigated through appropriate screening. Among CRC, RAS mutations (KRAS, NRAS, and BRAS) are considered to be diagnostic predictive markers (Goud et al. 2020). The antibody response to epidermal growth factor receptor (EGFR) corresponds with cancer severity and treatment response (Douillard et al. 2013; Vauthey et al. 2013; Mise et al. 2015). The carcinogenesis of CRC has been well studied at the molecular level, and studies of miRNAs with CRC have begun, and the molecular entities provide unique potential biomarkers for classifying tumors and predicting the various responses to active chemotherapy (Corté et al. 2012). Both miRNAs 143 and 145 have been identified as possible factors in colon tumorigenesis in CRC. The 143 and 145 miRNAs on chromosome 5 were shown to be at lower levels in colon cancer epithelial cells (Michael et al. 2003). The up- and downregulations in miRNA will be a crucial role in CRC development, and many miRNA abnormalities are correlated to p53 dysregulation, a tumor suppressor whose activity is diminished during colorectal carcinogenesis (Yang et al. 2009). Choi et al. (2019) examined the stool to determine the miRNA levels. When CRC patients were compared to healthy controls, 92a and 144 miRNAs were found to be differentially expressed with strong specificity and sensitivity. Yau et al. (2019) discovered fecal miRNAs (21 and 91a) and their combination as a viable noninvasive biomarker for CRC diagnosis. A previous study also observed elevated expression levels of miR-21 in the feces of CRC patients (Link et al. 2010). Increased serum levels of miR-21 were confirmed for CRC diagnostics for decade(s), and plasma levels of 7, 93, 378, and 409-3p for miR were also distinguishable in CRC versus controls (Zhu et al. 2017; Wikberg et al. 2018; Zanutto et al. 2014; Wang et al. 2015). A previous study from Japan found that miR-17-92a was associated with the recurrence of CRC in serum samples utilizing miRNA microarray analysis (Matsumura et al. 2015). A Chinese study discovered a panel of three miRNAs (19a-3p, 21-5p, and 425-5p) that might be used as a noninvasive biomarker in the identification of CRC using serum samples (Zhu et al. 2017). Increased levels of miR-141 in plasma samples were found in colon

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cancer patients with advanced stage IV, and their expression levels were found to be highly connected with a poor survival rate (Cheng et al. 2011).

7.2.3

Gastric Cancer

Gastric cancer (GC) is the fourth most frequent cancer and second leading cause of cancer death globally, with a male-to-female ratio of 2:1 (Van Cutsem et al. 2016). The mortality rate was determined to be 30% (Eusebi et al. 2020). Prior detection of GC is challenging because this malignancy is asymptomatic during the early stages and takes at least 7 months (Wagner et al. 2006). GC can be diagnosed in the initial stages using upper gastrointestinal imaging and endoscopy as an invasive technique. CEA, CA19-9, and CA72-4 are the tumor markers utilized for diagnosis and prognosis, but they lack sensitivity at an early stage (Feng et al. 2017). Cai et al. (2013) studies confirmed higher levels of 20a, 106b, and 221 miR in GC when compared with controls. The expression of 24-3p, 122-5p, 425-5p, 1180-3p, and 4632-3p miRNAs in plasma is considered a potential biomarker panel for diagnosing GC, and the combination of these biomarkers with gastroscopy could improve the early prediction and detection of GC (Zhu et al. 2019). In GC patients, miR-21 levels in serum and peripheral blood mononuclear cells were higher than in controls, suggesting that it could be exploited as a biomarker in the early and middle stages of the disease (Wu et al. 2015). The investigations of Liu et al. (2011) found that 1, 20a, 27a, 34, and 423 miRNAs were considered as a new panel of biomarkers for GC diagnosis. Higher serum levels of miR-378, alone or in addition with 187 and 371-5p miRNA levels, are anticipated to be a predictive biomarker for detecting GC in its early stages (Liu et al. 2012a). In GC patients, increased expression of miR-515-3p in serum and decreased expression of miR-141 in plasma has been confirmed in comparison to control participants (Han et al. 2019; Wang et al. 2019).

7.2.4

Glioblastoma

The most common and aggressive malignant primary brain tumor in adults is glioblastoma (GB) which is defined with histological features (Lah et al. 2021). Glioblastoma multiforme (GBM) is a grade IV tumor and is sometimes classified as GB. Other than age, the risk factors for the development of GB are poorly established. Males are affected more frequently than females (1.6:1), while whites are impacted more frequently than blacks (Wirsching et al. 2016). The miRNA signatures are intimately connected to the onset and progression of GB (Pottoo et al. 2021). Documented studies have established the critical function of miRNAs in GB resistance, and various miRNAs have been associated to GB pathogenesis in the processes of angiogenesis, metastasis, and tumor growth. Targeted mRNA regulates gene expression by binding directly to complementary sequences in the 30 UTR of mRNA (Ahmed et al. 2021). Computer tomography and magnetic resonance imaging are invasive and expensive procedures used to diagnose and monitor GB, and

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there is no innovative noninvasive biomarker to identify GB as of yet. A study from Wang et al. (2012) revealed altered levels of 21, 128, and 342-3p miRNAs in GBM plasma, and this similar panel of miRNAs did not improve in brain tumors and other types of GBM. MiRNA levels in plasma samples after surgery and radiation therapy are normalized and well correlated with glioma histological grading. According to Qu et al. (2015), the importance of miR-21 as a single biomarker exploited in the diagnosis of glioma in extracellular vesicles (EV) with high specificity and sensitivity has been highlighted. The 451-miRNA discovered in EV, on the other hand, is considered to be a GBM-related miRNA.

7.2.5

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a prominent cause of cancer death in the modern era, especially in patients with cirrhosis. Shifting evidence suggests that, in addition to viral hepatitis and alcohol-induced liver disease, the metabolic syndrome with nonalcoholic liver disease may be a major cause of HCC (Bruix et al. 2014). This liver cancer disease has been identified as the third leading cause of cancer deaths in the world (Finkelmeier et al. 2019). MiRNA have already attracted the attentions of biomarkers because to their important role in cancer development and prognosis. MiRNA dysregulation has been observed in a number of malignancies, and miRNAs as biomarkers have been used in HCC. Previous studies have found a correlation between miRNAs and HCC, with miR-222 being found to be deregulated and miR-224 being targeted as glycine-N-methyl transferase, a characteristic of 20-miRNA (Sathipati and Ho 2020). The transcription of pri-miRNA can be controlled by transcription factor genes that are dysregulated in HCC, such as c-Myc, which binds to upstream of miR-17 and upregulates the transcription of miR-17-92, a tumor-promoting polycistronic miRNA. The miRNA process is altered in HCC, and dysregulation leads to changes in the expression profile of target genes involved in the initiation and progression of HCC. Circular miRNAs that have been released will have an effect on HCC once they are in circulation (Borel et al. 2012; Nagy et al. 2018). Initially, alpha-fetoprotein (AFP) was considered as a biomarker for HCC detection, but it was later stated as one of the limitations because it was not found in minor cases of HCC (