MiR‐182 and miR‐203 induce mesenchymal to epithelial transition and self‐sufficiency of growth signals via repressing SNAI2 in prostate cells

Abstract

MicroRNAs play critical roles in tumorigenesis and metastasis. Here, we report the dual functions of miR-182 and miR-203 in our previously described prostate cell model. MiR-182 and miR-203 were completely repressed during epithelial to mesenchymal transition (EMT) from prostate epithelial EP156T cells to the progeny mesenchymal nontransformed EPT1 cells. Re-expression of miR-182 or miR-203 in EPT1 cells and prostate cancer PC3 cells induced mesenchymal to epithelial transition (MET) features. Simultaneously, miR-182 and miR-203 provided EPT1 cells with the ability to self-sufficiency of growth signals, a well-recognized oncogenic feature. Gene expression profiling showed high overlap of the genes affected by miR-182 and miR-203. SNAI2 was identified as a common target of miR-182 and miR-203. Knock-down of SNAI2 in EPT1 cells phenocopied reexpression of either miR-182 or miR-203 regarding both MET and self-sufficiency of growth signals. Strikingly, considerable overlaps of changed genes were found between the re-expression of miR-182/203 and knock-down of SNAI2. Finally, P-cadherin was identified as a direct target of SNAI2. We conclude that miR-182 and miR-203 induce MET features and growth factor independent growth via repressing SNAI2 in prostate cells. Our findings shed new light on the roles of miR-182/203 in cancer related processes.The breakdown of epithelial cell homeostasis with the loss of epithelial characteristics and the acquisition of a migratory phenotype, referred to as epithelial to mesenchymal transition (EMT) is a crucial event in tumor progression and endows cancer cells with invasive and metastatic competence.1 Prostate cancer is one of the most common male cancers in Western countries. In an attempt to transform benign prostate cells to malignant ones, we have observed typical EMT features in primary prostate basal EP156T cells.2 However, both EP156T and the progeny EPT1 cells lacked malignant features such as anchorage independent growth, resistance to apoptosis and independence of external growth factors. 2,3 This unique EMT cell model provides a good opportunity to understand the mechanisms of EMT and malignant transformation in vitro.MicroRNAs (miRNAs/miRs) are a large class of endogenous tiny regulatory RNAs that extensively regulate gene expression. MiRNAs function post-transcriptionally through imperfect base pairing with specific sequences in the 3 0 untranslated regions (UTRs) of target mRNAs leading to transcript degradation or translational inhibition. 4 The role of miRNAs depends not only on their specific mRNA targets but also upon their context, such as cell type, tissue or stage of development. MiRNAs are widely recognized as important in tumor progression, it has been considered that alterations in the expression of miRNAs might contribute to the pathogenesis of most human malignancies.5 However, most of these studies utilized cancer cells, examination of the function of miRNAs in premalignant cells is thus far limited.Exploiting our unique premalignant EPT1 cell model that ...

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