title: miR-130b-3p Modulates Epithelial-Mesenchymal Crosstalk in Lung Fibrosis by Targeting IGF-1.
abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal fibrotic lung disease with largely unknown etiology and pathogenesis. Evidence suggests microRNAs (miRNA) contribute to pathogenesis of IPF. In this study, we sought to identify miRNA expression signatures and determine the role of miR-130b-3p in lung fibrosis. The miRNA expression profile of the lungs from patients with IPF and normal donors was determined by Affymetrix microarray, and transcriptome with Affymetrix array. The functions and signal pathways as well as miRNA-mRNA networks were established by bioinformatics analysis. Luciferase assays and ELISA were used to confirm the miRNA target gene. The effect of miRNA-transfected epithelium on fibroblast activities was assessed using a co-culture system. The fibroblast activities were determined by qRT-PCR, western blotting, Transwell and BrdU assays. Seven miRNAs were significantly decreased in IPF lungs, with miR-130b-3p being the highest in the miRNA-mRNA network. Insulin-like growth factor (IGF-1) was a target gene of miR-130b-3p in the epithelium. miR-130b-3p inhibition in the epithelium induced collagen I expression and enhanced the proliferation and migration ability of fibroblast in co-culture systems, which mimicked the functions of exogenous IGF-1 on fibroblasts. Neutralizing IGF-1 with an antibody significantly reduced the modulatory effects of miR-130b-3p inhibitor-transfected epithelium on the activation of fibroblasts. Our results show that miR-130b-3p was downregulated in IPF lungs. miR-130b-3p downregulation contributed to the activation of fibroblasts and the dysregulated epithelial-mesenchymal crosstalk by promoting IGF-1 secretion from lung epithelium, suggesting a key regulatory role for this miRNA in preventing lung fibrosis.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, P.R. China.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, P.R. China.|National Clinical Research Centre for Respiratory Medicine, Beijing Hospital, Beijing 100730, P.R. China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medical Research, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Huang
authors.affiliation: Clinical Laboratory, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China.
authors.forename: Dong
authors.initials: D
authors.lastname: Leng
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, P.R. China.
authors.forename: Dingyuan
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Medicine Pulmonary Division and Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States of America.
authors.forename: Jiurong
authors.initials: J
authors.lastname: Liang
authors.affiliation: National Clinical Research Centre for Respiratory Medicine, Beijing Hospital, Beijing 100730, P.R. China.|Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, 100029, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, P.R. China.|Department of Medicine Pulmonary Division and Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States of America.
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, P.R. China.|Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, 100029, P.R. China.
authors.forename: Huaping
authors.initials: H
authors.lastname: Dai
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D002450:Cell Communication; D002465:Cell Movement; D049109:Cell Proliferation; D016000:Cluster Analysis; D018920:Coculture Techniques; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008954:Models, Biological; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D024042:Collagen Type I; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I