title: MicroRNA-146a modulates TGF-β1-induced phenotypic differentiation in human dermal fibroblasts by targeting SMAD4.
abstract: During wound healing and tissue repair the dermal fibroblast-to-myofibroblast transdifferentiation plays an important role, transforming growth factor-β1 (TGF-β1) is considered to be the main stimuli factor of transdifferentiation. MicroRNAs (miRNAs) have recently emerged as key post-transcriptional regulators of gene expression. The involvement of miRNAs and their roles in TGF-β1-induced myofibroblast transdifferentiation remains to be determined in detail. The current study found that the expression of miR-146a was upregulated in human dermal fibroblasts cells in response to TGF-β1 stimulation in dose-dependent manner by quantitative RT-PCR. Bioinformatic analyses predict that signaling effectors mothers against decapentaplegic protein 4 (SMAD4) is a miR-146a target gene. Luciferase assay demonstrated that miR-146a mimics suppressed SMAD4 3'-UTR reporter construct activity. Furthermore, miR-146a overexpression in dermal fibroblast did not decrease target mRNA levels, but significantly reduced target protein expression. In addition, dermal fibroblasts transfected with miR-146a mimics exhibited attenuated TGF-β1 -induced α-smooth muscle actin (α-SMA) expression compared with the control. This study demonstrated that miR-146a may function as a novel negative regulator to modulate myofibroblast transdifferentiation during TGF-β1 induction by targeting SMAD4.
authors.affiliation: Center of Plastic Surgery and Burn Repair, Beijing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Cui-Ling
authors.initials: CL
authors.lastname: Lu
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Cui
authors.forename: Yong-Liang
authors.initials: YL
authors.lastname: Hu
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Tian
authors.initials: T
authors.lastname: Ma
authors.forename: Da-Kai
authors.initials: DK
authors.lastname: Jiao
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Jia
mesh_terms: D000199:Actins / Q000096:biosynthesis; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D020405:Dermis / Q000187:drug effects / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D052816:Foreskin / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000199:Actins; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1