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

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

Author information

1
Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
2
Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
3
EA4483, Faculté de Médecine de Lille, Pole Recherche, Lille, France.

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

PMID:
26120970
DOI:
10.1111/1751-2980.12266
[Indexed for MEDLINE]

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