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

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.