[Frontiers in Bioscience, Elite, 12, 48-78, Jan 1, 2020]

Role of miRNA clusters in epithelial to mesenchymal transition in cancer

Vaibhav Shukla1, Divya Adiga1, Padacherri Vethil Jishnu1, Vinay Koshy Varghese1, Kapaettu Satyamoorthy1, Shama Prasada Kabekkodu1

1Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India


1. Abstract
2. Introduction
3. Molecular Pathogenesis of EMT
4. miRNA Cluster
    4.1. miRNA Cluster and EMT
    4.2. SLUG and miRNA cluster
    4.3. SNAIL and miRNA cluster
    4.4. TWIST and miRNA cluster
    4.5. ZEB and miRNA cluster
5. miRNA clusters and signaling pathways
    5.1. Tyrosine kinases pathway
    5.2. Integrin-linked kinase (ILK) pathway- integrin signaling
    5.3. Ras pathway
    5.4. Notch signaling pathway
    5.5. Wnt signaling pathway
    5.6. Hedgehog signaling pathway
6. Conclusion
7. Acknowledgments
8. References


Epithelial to mesenchymal transition (EMT) is a multistep biological process in which epithelial cells acquire characteristics of mesenchymal cells. Inappropriate activation of EMT contributes to the acquisition of pro-metastatic characteristics and cancer progression. EMT process involves the downregulation of epithelial markers (EpCAM, CDH1) and upregulation of mesenchymal markers (VIM, CDH2) and EMT-transcription factors (ZEB1/2, TWIST1/2, SNAI1, SLUG). MicroRNAs, a class of non-coding RNA post-transcriptionally govern gene expression by binding to the target mRNAs. A large proportion of miRNAs occur as miRNA clusters consisting of two or more miRNA coding genes. MiRNA clusters are reported to regulate diverse biological functions, including EMT. This comprehensive review discusses the role of miRNA clusters in EMT.


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Abbreviations: EMT, epithelial to mesenchymal transition; miRNA, microRNA; ZEB1, Zinc finger E-box binding homeobox 1; Wnt, -wingless; ECM , extra cellular matrix; Hh, Hedgehog; FOXO1, forkhead box protein O1; PTEN, phosphatase and tensin homolog; ECM, extra cellular matrix; CDH1, Cadherin 1; CTNBB1, Catenin Beta 1; RAC1, Rac family small GTPase1; RHO, Rhodopsin; CDC42, Cell division cycle 42; PAR, partition-defective; PATJ, Protein associated to tight junctions; MMP, matrix metalloproteinases; EMT-TFs, EMT-transcription factors ; TGF-β, transforming growth factor beta; RTKs, receptor tyrosine kinases; HIF1α, hypoxia-inducible factor 1α; JAK/STAT, Janus kinase2/signal transducer and activator of transcription; TNFα, tumor necrosis factor alpha; TNFR, TNF receptor superfamily member 1A; NFkB, nuclear factor kappa B subunit 11; IKB, IKappaB; IL6, interleukin 6; EGF , Epidermal growth factor; PI3K-AKT-mTOR, Phosphoinositide-3-Kinase- AKT Serine/Threonine Kinase 1-Mammalian Target Of Rapamycin; Ras-MAPK, Rat sarcoma-mitogen-activated protein kinase 1; MKK, mitogen-activated protein kinase kinase1; LOX, Lysyl oxidase; HIPK1, Homeodomain Interacting Protein Kinase 1; PTEN, phosphatase and tensin homolog; SOCS1,suppressor of Cytokine Signaling 1; CDKN1B, Cyclin-Dependent Kinase Inhibitor 1B; GHR, Growth Hormone Receptor; TRAF3, TNF Receptor Associated Factor 3; ASCL2, Achaete-Scute Family BHLH Transcription Factor 2; FOXF2, Forkhead Box F2; CCND1, cyclinD1; SSH1, Slingshot Protein Phosphatase 1; LIMK1, LIM Domain Kinase 1; FGFD4, fibroblast growth factor 4; SNAIL2, Snail Family Transcriptional Repressor 2; VIM, vimentin VIM; MDCK, madin-darby canine kidney; BRMS1L, breast cancer metastasis suppressor 1-like; ITGB1, integrin beta 1; KLF4, Kruppel-like factor 4; SNAIL1, Snail Family Transcriptional Repressor 1; MET, MET proto-oncogene; β-TRCP2, F-box and WD repeat domain containing 11; MTSS1, metastasis suppressor 1; TGIF2, TGFB induced factor homeobox; YWHAG, Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Gamma; TIMP3, TIMP metallopaptidase inhibitor 3; bHLH, basic helix-loop-helix; C19MC, chromosme19 miRNA cluster; SIP1, smad interacting protein 1; RREB1, Ras-responsive element-binding protein; PSAP, Prosaposin; GSK3β, glycogen synthase kinase 3 beta; MAGI2, membrane-associated guanylate kinase; CML, chronic myelogenous leukemia; ERK, extracellular-signal-regulated kinase; VEGF, vascular endothelial growth factor; IGF1R, insulin like growth factor 1 receptor; RAF, RAf-like-kinases; GBM, Glioblastoma; CYLD, CYLD lysine 63 deubiquitinase; RAL, RAL GTPase; RAC, RAC family small GTPase; PAK, P21 activated kinases; MLCP, myosin light chain phosphatase; MLC, Megalencephalic Leukoencephalopathy With Subcortical Cysts 1; HRAS, HRas proto-oncogene; NSCLC, non-small-cell lung carcinoma, GRB2, growth factor receptor bound protein 2; SOS, son of sevenless homolog; TRPS1, Transcriptional Repressor GATA Binding 1; HES1, Hes family transcription factor 1; BRAF, B-Raf proto-oncogene; DLK1, delta like non-canonical notch ligand; DIO3, iodothyronine deiodinase; POGLUT1, protein O-glucosyltransferase 1; LEF1, lymphoid enhancer binding factor 1; MTSS1, Metastasis suppressor protein 1; PTCH, Patched1; GLI, glioma-associated oncogene; JAG2, Jagged 2

Key Words: MicroRNA cluster, EMT, Signaling pathway, Cancer, EMT-TFs

Send correspondence to: Shama Prasada Kabekkodu, Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal-576104, Karnataka, India, Tel: 0820-2922058, Fax: 91-820-2571919, E-mail: shama.prasada@manipal.edu