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.
Highlights
Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events
Epithelial cells are characterized by the expression of epithelial (E)-cadherin, ZO-1, occludin, cytokeratins, claudins, and type IV collagen, while mesenchymal cells are characterized by vimentin, α-SMA, FSP-1, fibronectin, neural (N)-cadherin, and secretion of type I and III collagens
We have focused this review on dissecting the functional roles of microRNAs and long non-coding RNAs (lncRNAs) within two levels of EMT processes
Summary
Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. A second EMT process occurs during cardiac development after the initial epicardial layer formation and subsequent invasion into the developing ventricular chambers, involving similar upstream signaling pathways, i.e., TGF-β/BMP signaling [53,54,55,56,57], but curiously independently of Snail, at least in mice [58], and requiring additional regulatory player such as PDGF [59], Wt1 and Tbx18 [60,61] In addition to those developmental events in which EMT plays a fundamental role, EMT is determinant in several pathophysiological conditions, in particular in cancer. The regulatory roles of these ncRNAs in the expression and function of those transcription factors involved in the initiation of the EMT process are elucidated, and secondly, a report on the regulation of those proteins that effectively confer migratory capacities to those mesenchymal cells is provided
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