Z Gastroenterol 2011; 49 - P1_28
DOI: 10.1055/s-0030-1269478

Hepatocyte growth factor (HGF) acts as an antifibrotic mediator by prominent miRNA-29 induction

M Kwiecinski 1, N Elfimova 1, A Noetel 1, S Schievenbusch 2, HP Dienes 1, M Odenthal 3
  • 1Institute for Pathology, University Hospital of Cologne, Cologne
  • 2Institute of Pathology, University Hospital Cologne, Cologne
  • 3Institut für Pathologie, Universität Köln, Köln

Aims: MicroRNAs (miRNAs) are small noncoding RNAs, inhibiting gene expression by targeting the 3´untranslated region (3´-UTR) of transcripts. Previously, we have shown by miRNA expression profiling that miR-29a/b are differentially expressed after fibrogenesis. Hepatic stellate cells (HSC) are the major extracellular matrix (ECM) producing cells and furthermore they are involved in profibrogenic cytokine production such as transforming growth factor-ß (TGF-β). Hepatocyte growth factor (HGF), however, is known to exert antifibrotic activities, acting as an antagonist of TGF-β. In the present study, we now studied the influence of HGF on the expression of miR-29 and the regulation of extracellular matrix production by miR-29.

Methods: Several subtypes of collagens and miR-29a were quantified by RT-PCR after stimulation of HSC with HGF and TGF-β. The interaction of miR-29 members with the mRNA of the collagen subtypes were analysed by reporter assays. HSC-T6 were transfected with ago-miR-29 and synthesis of miR-29 targets were determined by RT-PCR and Western Blotting.

Results: HGF stimulation of HSC resulted in a predominant repression of collagens synthesis. Database analyses revealed miR-29 as a candidate which inhibits synthesis of various collagen subunits. Reporter assays identified the 3´-UTR of the collagens 1 and 4 subunits as prominent targets of miR-29a inhibition. Additionally, ago-miR-29a/b transfection of HSC resulted in a prominent decrease of collagen synthesis shown on transcript and on protein level. Furthermore, we could demonstrate that after stimulation of HSC with HGF, miR-29 was significantly upregulated, whereas the stimulation with TGF-β leads to a decreased level of miR29.

Conclusion: The antifibrotic impact of HGF resulting in inhibition of collagen synthesis is suggested to be due to HGF mediated upregulation of miR-29, that was characterized as an inhibitor of colllagen sysnthesis and secretion of profibrogenic mediators.