MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis

Arch Toxicol. 2018 Sep;92(9):2935-2946. doi: 10.1007/s00204-018-2278-9. Epub 2018 Aug 10.


MicroRNA (miRNA)-mediated gene regulation contributes to liver pathophysiology, including hepatic stellate cell (HSC) activation and fibrosis progression. Here, we investigated the role of miR-942 in human liver fibrosis. The expression of miR-942, HSC activation markers, transforming growth factor-beta pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI), as well as collagen deposition, were investigated in 100 liver specimens from patients with varying degree of hepatitis B virus (HBV)-related fibrosis. Human primary HSCs and the immortalized cell line (LX2 cells) were used for functional studies. We found that miR-942 expression was upregulated in activated HSCs and correlated inversely with BAMBI expression in liver fibrosis progression. Transforming growth factor beta (TGF-β) and lipopolyssacharide (LPS), two major drivers of liver fibrosis and inflammation, induce miR-942 expression in HSCs via Smad2/3 respective NF-κB/p50 binding to the miR-942 promoter. Mechanistically, the induced miR-942 degrades BAMBI mRNA in HSCs, thereby sensitizing the cells for fibrogenic TGF-β signaling and also partly mediates LPS-induced proinflammatory HSC fate. In conclusion, the TGF-β and LPS-induced miR-942 mediates HSC activation through downregulation of BAMBI in human liver fibrosis. Our study provides new insights on the molecular mechanism of HSC activation and fibrosis.

Keywords: HSCs; Liver fibrosis; TGF-β signaling; Viral hepatitis.

MeSH terms

  • Cells, Cultured
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology*
  • Humans
  • Lipopolysaccharides / pharmacology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / pathology*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • MicroRNAs / metabolism*
  • NF-kappa B p50 Subunit / genetics
  • NF-kappa B p50 Subunit / metabolism
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Receptor, Transforming Growth Factor-beta Type I / metabolism
  • Smad Proteins, Receptor-Regulated / genetics
  • Smad Proteins, Receptor-Regulated / metabolism
  • Transforming Growth Factor beta1 / pharmacology


  • BAMBI protein, human
  • Lipopolysaccharides
  • MIRN942 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • NF-kappa B p50 Subunit
  • Smad Proteins, Receptor-Regulated
  • Transforming Growth Factor beta1
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human