title: miR-92a regulates TGF-β1-induced WISP1 expression in pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form of idiopathic interstitial pneumonia. MicroRNAs (miRNAs), short, single-stranded RNAs that regulate protein expression in a post-transcriptional manner, have recently been demonstrated to contribute to IPF pathogenesis. We have previously identified WNT1-inducible signaling pathway protein 1 (WISP1) as a highly expressed pro-fibrotic mediator in IPF, but the underlying mechanisms resulting in increased WISP1 expression, remain elusive. Here, we investigated whether WISP1 is a target of miRNA regulation. We applied a novel supervised machine learning approach, which predicted miR-30a/d and miR-92a target sites in regions of the human WISP1 3'UTR preferentially bound by the miRNA ribonucleoprotein complex. Both miRNAs were decreased in IPF samples, whereas WISP1 protein was increased. We demonstrated further that transforming growth factor (TGF)-β1-induced WISP1 expression in primary lung fibroblasts in vitro and lung homogenates in vivo. Notably, miR-30a and miR-92a reversed TGF-β1-induced WISP1 mRNA expression in lung fibroblasts. Moreover, miR-92a inhibition increased WISP1 protein expression in lung fibroblasts. An inverse relationship for WISP1 and miR-92a was found in a TGF-β1 dependent lung fibrosis model in vivo. Finally, we found significantly increased WISP1 expression in primary IPF fibroblasts, which negatively correlated with miR-92a level ex vivo. Altogether, our findings indicate a regulatory role of miR-92a for WISP1 expression in pulmonary fibrosis.
authors: Comprehensive Pneumology Center, Helmholtz Zentrum Munchen, University Hospital, Ludwig-Maximilians University, Munich, Member of the German Center for Lung Research (DZL), Germany.
authors: Barbara
authors: B
authors: Berschneider
authors: Department of Genome-oriented Bioinformatics, Technische Universität München, Center of Life and Food Science, Freising Weihenstephan, Germany.
authors: Daniel C
authors: DC
authors: Ellwanger
authors: Comprehensive Pneumology Center, Helmholtz Zentrum Munchen, University Hospital, Ludwig-Maximilians University, Munich, Member of the German Center for Lung Research (DZL), Germany.
authors: Hoeke A
authors: HA
authors: Baarsma
authors: Comprehensive Pneumology Center, Helmholtz Zentrum Munchen, University Hospital, Ludwig-Maximilians University, Munich, Member of the German Center for Lung Research (DZL), Germany.
authors: Cedric
authors: C
authors: Thiel
authors: Department of Medicine, McMaster University, Firestone Institute for Respiratory Health, Hamilton, ON, Canada.
authors: Chiko
authors: C
authors: Shimbori
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Eric S
authors: ES
authors: White
authors: Department of Medicine, McMaster University, Firestone Institute for Respiratory Health, Hamilton, ON, Canada.
authors: Martin
authors: M
authors: Kolb
authors: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, Munich, Germany.
authors: Peter
authors: P
authors: Neth
authors: Comprehensive Pneumology Center, Helmholtz Zentrum Munchen, University Hospital, Ludwig-Maximilians University, Munich, Member of the German Center for Lung Research (DZL), Germany. Electronic address: melanie.koenigshoff@helmholtz-muenchen.de.
authors: Melanie
authors: M
authors: Königshoff
mesh_terms: D000818:Animals; D001185:Artificial Intelligence; D055511:CCN Intercellular Signaling Proteins / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051381:Rats; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; C546086:MIRN30b microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D053773:Transforming Growth Factor beta1
keywords: CCN4; Pulmonary fibrosis; WISP1; miR-30; miR-92a