title: MicroRNA-31 is a positive modulator of endothelial-mesenchymal transition and associated secretory phenotype induced by TGF-β.
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.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.|Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katsura
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, 76-417, Cambridge, MA, 02139, USA.
authors.forename: Hiroshi I
authors.initials: HI
authors.lastname: Suzuki
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Mihira
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.|Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-city, Tokyo, 192-0392, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Watabe
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010641:Phenotype; D026723:Polyadenylation / Q000187:drug effects; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D055571:Secretory Pathway / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; D000199:Actins; D035683:MicroRNAs; C539917:Mirn31 microRNA, mouse; C511173:Mrtfa protein, mouse; D051567:Proto-Oncogene Proteins c-vav; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C496622:Vav3 protein, mouse