Premium
miR ‐30c and miR ‐193 are a part of the TGF ‐β‐dependent regulatory network controlling extracellular matrix genes in liver fibrosis
Author(s) -
Roy Sanchari,
Benz Fabian,
Vargas Cardenas David,
Vucur Mihael,
Gautheron Jeremie,
Schneider Anne,
Hellerbrand Claus,
Pottier Nicolas,
Alder Jan,
Tacke Frank,
Trautwein Christian,
Roderburg Christoph,
Luedde Tom
Publication year - 2015
Publication title -
journal of digestive diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.684
H-Index - 51
eISSN - 1751-2980
pISSN - 1751-2972
DOI - 10.1111/1751-2980.12266
Subject(s) - microrna , fibrosis , hepatic stellate cell , extracellular matrix , downregulation and upregulation , hepatic fibrosis , transforming growth factor , cancer research , gene silencing , microarray analysis techniques , microarray , medicine , gene expression , microbiology and biotechnology , biology , gene , pathology , genetics
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 ( HSC s). Finally, predicted targets were assessed for their roles in fibrosis by transfecting murine HSC s with mi RNA mimics. Results Microarray analysis in murine fibrotic livers revealed a panel of 44 dysregulated miRNA s. In addition to previously established miRNAs known to be regulated in liver fibrosis in a TGF‐β‐ dependent manner (e.g., mi R ‐29, mi R ‐133), mi R ‐193 and mi R ‐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 miRNA s in HSC s. Finally, we identified TGF ‐ β2 and SNAIL 1 , 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 miRNA s modifying the TGF ‐β‐dependent regulation of extracellular matrix‐related genes in HSC s in the manifestation and resolution of liver fibrosis.