MicroRNA‐31 is a positive modulator of endothelial–mesenchymal transition and associated secretory phenotype induced by TGF‐β. (10th December 2015)

• Record Type: Journal Article
• Authors: Katsura, Akihiro; Suzuki, Hiroshi I.; Ueno, Toshihide; Mihira, Hajime; Yamazaki, Tomoko; Yasuda, Takahiko; Watabe, Tetsuro; Mano, Hiroyuki; Yamada, Yoshitsugu; Miyazono, Kohei
• Is Part Of: Genes to cells. Volume 21:Number 1(2016:Jan.)
• Page Start: 99
• Page End: 116
• Publication Date: 2015-12-10
• Subjects: Cytogenetics -- Periodicals; Cells -- Mechanical properties -- Periodicals; Molecular genetics -- Periodicals; Genes -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Biomechanics -- Periodicals; 571.6
• DOI: 10.1111/gtc.12323
• Languages: English
• ISSNs: 1356-9597

Abstract

Abstract : Transforming growth factor‐β (TGF‐β) plays central roles in endothelial–mesenchymal transition (EndMT) involved in development and pathogenesis. Although EndMT and epithelial–mesenchymal transition are similar processes, roles of microRNAs in EndMT are largely unknown. Here, we report that constitutively active microRNA‐31 (miR‐31) is a positive regulator of TGF‐β‐induced EndMT. 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 EndMT. 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 EndMT‐associated unique secretory phenotype (EndMT‐SP) characterized by induction of multiple inflammatory chemokines and cytokines including CCL17, CX3CL1, 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 EndMT. These data confirm that constitutively active microRNAs, as well as inducible microRNAs, serve as phenotypic modifiers interconnected with transcriptome dynamics during EndMT. Abstract : microRNA‐31 (miR‐31) was identified as a positive regulator of endothelial–mesenchymal transition (EndMT) and EndMT‐associated unique secretory phenotype induced by TGF‐β. miR‐31 targets negative regulators of MRTF‐A and inflammatory response, VAV3 and Stk40. Interestingly, TGF‐β induces shortening of Stk40 3′UTR by alternative polyadenylation and trimming of internal poly(A) sequence in the 3′UTR and enhances the target efficiency of Stk40 for miR‐31 to suppress Stk40.