miR-30c and miR-193 are a part of the TGF-β-dependent regulatory network controlling extracellular matrix genes in liver fibrosis

J Dig Dis. 2015 Sep;16(9):513-24. doi: 10.1111/1751-2980.12266.

Abstract

Objective: MicroRNAs (miRNAs) have recently emerged as novel regulators in liver fibrosis. miR-30c and miR-193 are involved in fibrotic remodeling processes and cancer development, respectively. This study aimed to explore the role of miR-30c and miR-193 in liver fibrosis.

Methods: The regulation of miRNAs in carbon tetrachloride-induced liver fibrosis was analyzed by microarray. Expression patterns of miR-193 and miR-30c were further confirmed in fibrotic liver samples obtained from two murine models of hepatic fibrosis and human tissues. On a functional level, miRNA levels were analyzed in the context of transforming growth factor (TGF-β) mediated activation of hepatic stellate cells (HSCs). Finally, predicted targets were assessed for their roles in fibrosis by transfecting murine HSCs with miRNA mimics.

Results: Microarray analysis in murine fibrotic livers revealed a panel of 44 dysregulated miRNAs. In addition to previously established miRNAs known to be regulated in liver fibrosis in a TGF-β-dependent manner (e.g., miR-29, miR-133), miR-193 and miR-30c were observed to be specifically downregulated not only in experimental hepatofibrogenesis but also in human liver fibrosis, while they showed a reciprocal expression pattern after recovery from liver fibrosis. Functional experiments confirmed the TGF-β-dependent downregulation of these respective new miRNAs in HSCs. Finally, we identified TGF-β2 and SNAIL1, important regulators of extracellular matrix, as potential target genes of miR-193 and miR-30 in liver fibrosis.

Conclusion: These results suggest that miR-30 and miR-193 are members of a network of miRNAs modifying the TGF-β-dependent regulation of extracellular matrix-related genes in HSCs in the manifestation and resolution of liver fibrosis.

Keywords: hepatic stellate cells; liver fibrosis; miR-193; miR-30; microRANs; transforming growth factor beta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Area Under Curve
  • Biomarkers / blood
  • Carbon Tetrachloride
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Extracellular Matrix / genetics*
  • Extracellular Matrix / metabolism
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism
  • Mice
  • MicroRNAs / blood*
  • MicroRNAs / genetics*
  • Oligonucleotide Array Sequence Analysis
  • ROC Curve
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transfection
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / pharmacology

Substances

  • Biomarkers
  • MIRN193 microRNA, human
  • MIRN193 microRNA, mouse
  • MIRN30 microRNA, human
  • MicroRNAs
  • Mirn30d microRNA, mouse
  • SNAI1 protein, human
  • Snai1 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • Carbon Tetrachloride