title: MiR-21/Smad 7 signaling determines TGF-β1-induced CAF formation.
abstract: How TGF-β1-mediated signaling pathways are finely tuned to orchestrate the generation of carcinoma-associated fibroblasts (CAFs) is poorly understood. Here, we demonstrate that miR-21 and the signaling of its target Smad 7 determine TGF-β1-induced CAF formation. In primary cultured fibroblasts, mature miR-21 increases after TGF-β1 treatment, whereas the Smad 7 protein level decreases. MiR-21 binds to the 3' UTR of Smad7 mRNA and inhibits its translation, rather than causing its degradation. Most importantly, Smad 7 is bound to Smad 2 and 3, which are thought to competitively bind to TGFBR1, and prevents their activation upon TGF-β1 stimulation. The depletion of miR-21 or the overexpression of Smad 7 blocks TGF-β1-induced CAF formation, whereas the overexpression of miR-21 or the depletion of Smad 7 promotes CAF formation, even without TGF-β1 stimulation. Collectively, these findings clearly demonstrate that miR-21 and Smad7 are critical regulators of TGF-β1 signaling during the induction of CAF formation.
authors.affiliation: Department of Biochemistry & Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Li
authors.forename: Daoxiang
authors.initials: D
authors.lastname: Zhang
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Wang
authors.forename: Pan
authors.initials: P
authors.lastname: Sun
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Hou
authors.forename: James
authors.initials: J
authors.lastname: Larner
authors.forename: Wujun
authors.initials: W
authors.lastname: Xiong
authors.forename: Jun
authors.initials: J
authors.lastname: Mi
mesh_terms: D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010442:Peptide Chain Initiation, Translational; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D047368:Tumor Burden; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1