title: MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation.
abstract: Although microRNAs (miRs) have been well recognized to play an important role in the pathogenesis of organ fibrosis, there is a lack of evidence as to whether miRs directly regulate the differentiation of myofibroblasts, the putative effector cells during pathological fibrogenesis. In this study, we found that levels of miR-27a-3p were up-regulated in transforming growth factor-β1-treated human lung fibroblasts in a Smad2/3-dependent manner and in fibroblasts isolated from lungs of mice with experimental pulmonary fibrosis. However, both basal and transforming growth factor-β1-induced expression of miR-27a-3p were reduced in lung fibroblasts from patients with idiopathic pulmonary fibrosis compared with that from normal control subjects. Overexpression of miR-27a-3p inhibited, whereas knockdown of miR-27a-3p enhanced, the differentiation of lung fibroblasts into myofibroblasts. We found that miR-27a-3p directly targeted the phenotypic marker of myofibroblasts, α-smooth muscle actin, and two key Smad transcription factors, Smad2 and Smad4. More importantly, we found that therapeutic expression of miR-27a-3p in mouse lungs through lentiviral delivery diminished bleomycin-induced lung fibrosis. In conclusion, our data suggest that miR-27a-3p functions via a negative-feedback mechanism in inhibiting lung fibrosis. This study also indicates that targeting miR-27a-3p is a novel therapeutic approach to treat fibrotic organ disorders, including lung fibrosis.
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Huachun
authors.initials: H
authors.lastname: Cui
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Sami
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Na
authors.initials: N
authors.lastname: Xie
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Ge
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Liu
authors.affiliation: 2 Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sadis
authors.initials: S
authors.lastname: Matalon
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: 1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology*; D016086:Lentivirus / Q000378:metabolism; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051899:Smad2 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D051899:Smad2 Protein; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1
keywords: Smad; lung fibrosis; microRNA-27a-3p; myofibroblast; α-smooth muscle actin