title: Transforming growth factor-β1 selectively inhibits hepatocyte growth factor expression via a micro-RNA-199-dependent posttranscriptional mechanism.
abstract: Hepatocyte growth factor (HGF) is a multipotent endogenous repair factor secreted primarily by mesenchymal cells with effects on cells expressing its receptor, Met. HGF promotes normal tissue regeneration and inhibits fibrotic remodeling in part by promoting proliferation and migration of endothelial and epithelial cells and protecting these cells from apoptosis. HGF also inhibits myofibroblast proliferation. The profibrotic cytokine transforming growth factor beta 1 (TGF-β1) suppresses HGF expression but not the expression of NK2, an HGF splice variant that antagonizes HGF-induced proliferation. We investigated the mechanism for differential regulation of HGF and NK2 by TGF-β1. TGF-β1 down-regulated HGF in primary human adult pulmonary fibroblasts (HLFb) and increased the expression of miR-199a-3p, a microRNA (miRNA) associated with fibrotic remodeling. HGF and NK2 contain completely different 3' untranslated regions (UTRs), and we determined that miR-199a-3p targeted HGF mRNA for suppression but not NK2. A pre-miR-199 mimic inhibited the expression of a luciferase reporter harboring the HGF 3' UTR but not a pmirGLO reporter containing the NK2 3' UTR. In contrast, an anti-miRNA inhibitor specific for miR-199a-3p prevented TGF-β1-induced reduction of both HGF mRNA and HGF protein secretion. Taken together, these findings demonstrate that HGF is distinctly regulated at the posttranscriptional level from its antagonist NK2.
authors: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors: Ognoon
authors: O
authors: Mungunsukh
authors: Regina M
authors: RM
authors: Day
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D001483:Base Sequence; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052816:Foreskin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008156:Luciferases; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; C066855:HGF protein, human; D035683:MicroRNAs; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; C531408:mirn199 microRNA, human; D017228:Hepatocyte Growth Factor; D008156:Luciferases
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