Abstract
Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, amongst others. Classically, the morphological change from epithelial to mesenchymal phenotype is characterized by the appearance or loss of a group of proteins which have come to be recognized as markers of the EMT process. As with all proteins, these molecules are controlled at the transcriptional and translational level by transcription factors and microRNAs, respectively. A group of developmental transcription factors form the backbone of the EMT cascade and a large body of evidence shows that microRNAs are heavily involved in the successful coordination of mesenchymal transformation and vice versa, either by suppressing the expression of different groups of transcription factors, or otherwise acting as their functional mediators in orchestrating EMT. This article dissects the contribution of microRNAs to EMT and analyzes the molecular basis for their roles in this cellular process. Here, we emphasize their interaction with core transcription factors like the zinc finger enhancer (E)-box binding homeobox (ZEB), Snail and Twist families as well as some pluripotency transcription factors.
Highlights
Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis
The morphological change from epithelial to mesenchymal phenotype is characterized by the appearance or loss of a group of proteins which have come to be recognized as markers of the EMT process
A group of developmental transcription factors form the backbone of the EMT cascade and a large body of evidence shows that microRNAs are heavily involved in the successful coordination of mesenchymal transformation and vice versa, either by suppressing the expression of different groups of transcription factors, or otherwise acting as their functional mediators in orchestrating EMT
Summary
The zinc finger E-box binding homeobox (ZEB) family comprises two members, ZEB1 and ZEB2 ( commonly known as smad interacting protein 1 (SIP1)). Kim and colleagues demonstrated that p53 loss-of-function or mutations promoted EMT by de-repressing SNAI1 protein expression and activity in multiple cancer cell lines This was attributed to a decrease in miRNA-34 levels (miR-34a, miR-34b, and miR-34c), which suppressed SNAI1 directly by binding to a highly conserved region of its 31UTR. In dissecting the miRNAs that were differentially expressed in gastric cancer, Li and colleagues identified miR-223 to be overexpressed in metastatic gastric cancer cells only, and stimulated migration and invasion in non-metastatic gastric cancer cells They discovered that miR-223 was induced by TWIST via binding to an E-box located in its core promoter, binding to the 31UTR of erythrocyte membrane protein band 4.1-like 3 (EPB41L3) and suppressing its translation [161]. Other documented direct inhibitors of TWIST1 include miR-520d-5p [172], miR-137 [173], miR-33a [174,175], miR-186 [176] and miR-1-1 [177]
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