Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs

Abstract

Epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), are essential during development and in the regulation of stem cell pluripotency, yet these processes are also activated in pathological contexts, such as in fibrosis and cancer progression. In EMT and MET, diverse signaling pathways cooperate in the initiation and progression of the EMT and MET programs, through regulation at transcriptional, post-transcriptional, translational, and post-translational levels. MicroRNAs recently emerged as potent regulators of EMT and MET, with their abilities to target multiple components involved in epithelial integrity or mesenchymal traits. By affecting EMT and MET processes, microRNAs are involved in the regulation of stem cell pluripotency and the control of tumor progression.

Figure 1

MicroRNAs in EMT and MET. EMT is characterized by a disassembly of cell–cell junctions, loss of epithelial polarity, and reorganization of actin cytoskeleton. In addition to a decrease in epithelial marker expression, increases in expression of mesenchymal markers and invasive behavior are observed in cells undergoing EMT. The changes in gene expression programs are activated by families of transcription factors. MicroRNAs suppress production of these transcription factors as well as multiple markers and components that define the epithelial or mesenchymal characteristics. These microRNAs can therefore promote EMT (orange) or repress EMT and enhance MET programs (green).

Figure 2

Different mechanisms of action of microRNAs in regulating EMT. Three distinct mechanisms of regulation of EMT components by microRNAs can be discerned. (a) Two distinct microRNAs can cooperate to regulate the expression of a single transcript by targeting different sites in the transcript’s 3′UTR. (b) One single microRNA can regulate multiple EMT components. (c) Double feedback loops are observed when the expression of microRNA is targeted and downregulated by its own EMT transcription factor target.

Figure 3

MicroRNAs regulate EMT-associated and MET-associated stem cell pluripotency and cancer progression. (a) The induction of pluripotent stem cells requires the acquisition of epithelial characteristics and is initiated by an MET event. By inhibiting EMT and enhancing MET programs (green), microRNAs can enhance reprogramming and stem cell pluripotency. (b) EMT and MET programs have been associated with cancer progression. Therefore, microRNAs that regulate EMT or MET programs can present oncogenic (orange) or tumor-suppressive roles (green). The presence of cancer stem cells that arise from EMT events within a population of tumor cells can also be regulated by the action of microRNAs. Therefore, blocking oncogenic microRNAs or expressing tumor-suppressive microRNAs represent potent strategies against tumor progression.