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

Genes Cells. 2016 Jan;21(1):99-116. doi: 10.1111/gtc.12323. Epub 2015 Dec 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Actins / metabolism
  • Animals
  • Base Sequence
  • Cell Line
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelium / cytology
  • Endothelium / drug effects*
  • Endothelium / metabolism
  • Epithelial-Mesenchymal Transition / drug effects*
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation / drug effects
  • Gene Regulatory Networks / drug effects
  • Mesoderm / cytology
  • Mesoderm / drug effects*
  • Mesoderm / metabolism*
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Phenotype
  • Polyadenylation / drug effects
  • Proto-Oncogene Proteins c-vav / metabolism
  • Secretory Pathway / drug effects*
  • Trans-Activators / metabolism
  • Transcriptome / drug effects
  • Transcriptome / genetics
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology


  • 3' Untranslated Regions
  • Actins
  • MicroRNAs
  • Mirn31 microRNA, mouse
  • Mrtfa protein, mouse
  • Proto-Oncogene Proteins c-vav
  • Trans-Activators
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Vav3 protein, mouse

Associated data

  • GENBANK/GSE70207