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Milosevic, J.* ; Pandit, K.* ; Magister, M.* ; Rabinovich, E.* ; Ellwanger, D.C. ; Yu, G.* ; Vuga, L.J.* ; Weksler, B.* ; Benos, P.V.* ; Gibson, K.F.* ; McMillan, M.* ; Kahn, M.* ; Kaminski, N.*

Profibrotic role of miR-154 in pulmonary fibrosis.

Am. J. Respir. Cell Mol. Biol. 47, 879-887 (2012)
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In this study, we explored the regulation and the role of up-regulated microRNAs in idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease of unknown origin. We analyzed the expression of microRNAs in IPF lungs and identified 43 significantly up-regulated microRNAs. Twenty-four of the 43 increased microRNAs were localized to the chromosome 14q32 microRNA cluster. We validated the increased expression of miR-154, miR-134, miR-299-5p, miR-410, miR-382, miR-409-3p, miR-487b, miR-31, and miR-127 by quantitative RT-PCR and determined that they were similarly expressed in embryonic lungs. We did not find evidence for differential methylation in this region, but analysis of transcription factor binding sites identified multiple SMAD3-binding elements in the 14q32 microRNA cluster. TGF-β1 stimulation of normal human lung fibroblasts (NHLF) caused up-regulation of microRNAs on chr14q32 that were also increased in IPF lungs. Chromatin immunoprecipitation confirmed binding of SMAD3 to the putative promoter of miR-154. Mir-154 was increased in IPF fibroblasts, and transfection of NHLF with miR-154 caused significant increases in cell proliferation and migration. The increase in proliferation induced by TGF-β was not observed when NHLF or IPF fibroblasts were transfected with a mir-154 inhibitor. Transfection with miR-154 caused activation of the WNT pathway in NHLF. ICG-001 and XAV939, inhibitors of the WNT/β-catenin pathway, reduced the proliferative effect of miR-154. The potential role of miR-154, one of multiple chr14q32 microRNA cluster members up-regulated in IPF and a regulator of fibroblast migration and proliferation, should be further explored in IPF.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter idiopathic pulmonary fibrosis; microRNA; TGF-beta; WNT/beta-caterin; developmental pathways; Keratinocyte Growth-factor ; Microrna Gene-cluster ; Wnt Signaling Pathway ; Lung Fibroblasts ; Tgf-beta ; Inhibition ; Cancer ; Transcription ; Activation ; Mechanisms
Sprache englisch
Veröffentlichungsjahr 2012
HGF-Berichtsjahr 2012
ISSN (print) / ISBN 1044-1549
e-ISSN 1535-4989
Zeitschrift American Journal of Respiratory Cell and Molecular Biology
Quellenangaben Band: 47, Heft: 6, Seiten: 879-887 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Bioinformatics and Systems Biology (IBIS)
POF Topic(s) 30505 - New Technologies for Biomedical Discoveries
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503700-001
PubMed ID 23043088
DOI 10.1165/rcmb.2011-0377OC
WOS ID WOS:000314406800019
Scopus ID 84870508377
Erfassungsdatum 2012-12-07
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