Abstract
BackgroundmicroRNA-122 (miR-122) is the most abundant and specific miRNA in the liver. It acts as an important tumor suppressor in hepatocellular carcinoma (HCC) through regulating its target genes, but details of its own regulation are largely unknown. Farnesoid X receptor (FXR), a transcription factor with multiple functions, plays an important role in protecting against liver carcinogenesis, but it is unclear whether the anti-HCC effect of FXR is involved in the regulation of miR-122.MethodsThe levels of miR-122 and FXR in HCC tissues and cell lines were examined by quantitative real-time PCR (qRT-PCR). qRT-PCR was also used to detect the expression of miR-122 target genes at mRNA level, while Western blotting was used to analyze that of their protein products. The effect of FXR on the transcriptional activity of miR-122 promoter was evaluated by a luciferase reporter assay. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay were performed to identify the FXR binding site within miR-122 promoter region. The cell proliferation was analyzed by a CCK-8 assay. The influence of FXR on tumor growth and miR-122 expression in vivo was monitored using HCC xenografts in nude mice.ResultsThe expression of FXR was positively correlated with that of miR-122 in HCC tissues and cell lines. Activation of FXR in HCC cells upregulated miR-122 expression and in turn downregulated the expression of miR-122 target genes including insulin-like growth factor-1 receptor and cyclin G1. FXR bound directly to the DR2 element (−338 to −325) in miR-122 promoter region, and enhanced the promoter’s transcriptional activity. Functional experiments showed that the FXR-mediated upregulation of miR-122 suppressed the proliferation of HCC cells in vitro and the growth of HCC xenografts in vivo.ConclusionsmiR-122 is a novel target gene of FXR, and the upregulation of miR-122 by FXR represses the growth of HCC cells, suggesting that FXR may serve as a key transcriptional regulator for manipulating miR-122 expression, and the FXR/miR-122 pathway may therefore be a novel target for the treatment of HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0427-9) contains supplementary material, which is available to authorized users.
Highlights
MicroRNA-122 is the most abundant and specific miRNA in the liver
Functional experiments showed that Farnesoid X receptor (FXR)-mediated upregulation of miR-122 suppressed the proliferation of hepatocellular carcinoma (HCC) cells in vitro and the growth of HCC xenografts in vivo. These results suggest that FXR may serve as a key transcriptional regulator for manipulating miR-122 expression, and that the FXR/miR-122 pathway may be a novel target for the treatment of HCC
FXR upregulates miR-122 expression and in turn downregulates the expression of miR-122 target genes in HCC cells To investigate the regulation of miR-122 by FXR, Hep3B cells were treated with the FXR agonist GW4064, the expression of miR-122 and its target genes including insulin-like growth factor-1 receptor (IGF-1R) and cyclin G1 were examined by quantitative real-time PCR (qRT-PCR) and Western blotting
Summary
MicroRNA-122 (miR-122) is the most abundant and specific miRNA in the liver. It acts as an important tumor suppressor in hepatocellular carcinoma (HCC) through regulating its target genes, but details of its own regulation are largely unknown. It has been shown to provide protection against liver carcinogenesis through regulating tumorrelated genes such as gankyrin, nuclear factor (NF)-κB, Nmyc downstream regulated gene 2 (NDRG2), p53, and carbohydrate response element binding protein [19,20,21,22,23]. It is unclear whether the anti-HCC effect of FXR is involved in the regulation of miR-122
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