Micro RNA-31 is a positive modulator of endothelial-mesenchymal transition and associated secretory phenotype induced by TGF-β.

Transforming growth factor-β ( TGF-β) plays central roles in endothelial-mesenchymal transition (End MT) involved in development and pathogenesis. Although End MT and epithelial-mesenchymal transition are similar processes, roles of micro RNAs in End MT are largely unknown. Here, we report that constitutively active micro RNA-31 (miR-31) is a positive regulator of TGF-β-induced End MT. Although the expression is not induced by TGF-β, miR-31 is required for induction of mesenchymal genes including α- SMA, actin reorganization and MRTF-A activation during End MT. We identified VAV3, a regulator of actin remodeling and MRTF-A activity, as a miR-31 target. Global transcriptome analysis further showed that miR-31 positively regulates End MT-associated unique secretory phenotype (End MT- SP) characterized by induction of multiple inflammatory chemokines and cytokines including CCL17, CX3 CL1, CXCL16, IL-6 and Angptl2. As a mechanism for this phenomenon, TGF-β and miR-31 suppress Stk40, a negative regulator of NF-κB pathway. Interestingly, TGF-β induces alternative polyadenylation ( APA)-coupled miR-31-dependent Stk40 suppression without concomitant miR-31 induction, and APA-mediated exclusion of internal poly(A) sequence in Stk40 3′ UTR enhances target efficiency of Stk40. Finally, miR-31 functions as a molecular hub to integrate TGF-β and TNF-α signaling to enhance End MT. These data confirm that constitutively active micro RNAs, as well as inducible micro RNAs, serve as phenotypic modifiers interconnected with transcriptome dynamics during End MT. [ABSTRACT FROM AUTHOR]