Functional Role of Non-Coding RNAs during Epithelial-To-Mesenchymal Transition

Abstract

Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. It is characterized by the progressive loss of cell-to-cell contacts and actin cytoskeletal rearrangements, leading to filopodia formation and the progressive up-regulation of a mesenchymal gene expression pattern enabling cell migration. Epithelial-to-mesenchymal transition is already observed in early embryonic stages such as gastrulation, when the epiblast undergoes an EMT process and therefore leads to the formation of the third embryonic layer, the mesoderm. Epithelial-to-mesenchymal transition is pivotal in multiple embryonic processes, such as for example during cardiovascular system development, as valve primordia are formed and the cardiac jelly is progressively invaded by endocardium-derived mesenchyme or as the external cardiac cell layer is established, i.e., the epicardium and cells detached migrate into the embryonic myocardial to form the cardiac fibrous skeleton and the coronary vasculature. Strikingly, the most important biological event in which EMT is pivotal is cancer development and metastasis. Over the last years, understanding of the transcriptional regulatory networks involved in EMT has greatly advanced. Several transcriptional factors such as Snail, Slug, Twist, Zeb1 and Zeb2 have been reported to play fundamental roles in EMT, leading in most cases to transcriptional repression of cell–cell interacting proteins such as ZO-1 and cadherins and activation of cytoskeletal markers such as vimentin. In recent years, a fundamental role for non-coding RNAs, particularly microRNAs and more recently long non-coding RNAs, has been identified in normal tissue development and homeostasis as well as in several oncogenic processes. In this study, we will provide a state-of-the-art review of the functional roles of non-coding RNAs, particularly microRNAs, in epithelial-to-mesenchymal transition in both developmental and pathological EMT.

Helicobacter pylori‐activated gastric fibroblasts induce epithelial‐mesenchymal transition of gastric epithelial cells in vitro in a TGF‐β‐dependent manner

“…A large number of growth factors and their activated transduction pathways have been implicated in EMT including the loss of E‐cadherin, acquiring N‐cadherin, and induction of cell migration and invasion . Increased levels of TGF‐β in the secretome of Hp ‐activated gastric fibroblasts indicate that this cytokine could mediate the phenotypic shifts undergone by gastric epithelial cells, which leads to E‐cadherin downregulation in RGM‐1 cells due to its transcriptional repression and decreases proliferation rates of RGM‐1 cells. In our hands, this could be due to the reprogramming of RGM‐1 cells toward the mobile phenotype.…”

Molecular Mechanisms in Clear Cell Renal Cell Carcinoma: Role of miRNAs and Hypermethylated miRNA Genes in Crucial Oncogenic Pathways and Processes

“…The number of publications aimed at identifying target genes and signaling pathways that involve miRNAs has increased (Reddy, 2015; Dragomir et al, 2018; Gattolliat et al, 2018). miRNAs are important positive or negative regulators of all processes characteristic of the pathogenesis of tumors, which include control of the cell cycle, apoptosis, neo-angiogenesis, tissue invasion, and metastasis (Exposito-Villen et al, 2018; Goradel et al, 2018; Kashyap et al, 2018; Mens and Ghanbari, 2018).…”

KLF5 regulates epithelial-mesenchymal transition of liver cancer cells in the context of p53 loss through miR-192 targeting of ZEB2

“…miRNAs are noncoding small RNAs that usually silence or repress gene expression by targeting the 3ʹ untranslated regions (UTRs) of mRNAs. Increasing numbers of miRNAs have been identified as negative regulators of EMT [ 29 , 30 ], and many of the miRNAs engaged in targeting EMT-TFs are transcriptionally activated by p53 [ 27 , 28 , 31 ]. For example, p53 can regulate EMT through the targeting of ZEB1 by miR-200s and the targeting of ZEB2 by miR-192 [ 25 , 32 , 33 ].…”