RRC ID 35947
Author Katsura A, Suzuki HI, Ueno T, Mihira H, Yamazaki T, Yasuda T, Watabe T, Mano H, Yamada Y, Miyazono K.
Title MicroRNA-31 is a positive modulator of endothelial-mesenchymal transition and associated secretory phenotype induced by TGF-β.
Journal Genes Cells
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.
Volume 21(1)
Pages 99-116
Published 2016-1
DOI 10.1111/gtc.12323
PMID 26663584
MeSH 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 Mesoderm / secretion* 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
IF 2.048
Times Cited 7
WOS Category GENETICS & HEREDITY CELL BIOLOGY
Resource
DNA material pENTR4-H1 (RDB04395) CS-RfA-EG (RDB04391) pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393).