Epigenetic repression of miR-132 expression by the hepatitis B virus x protein in hepatitis B virus-related hepatocellular carcinoma.

Hepatitis B virus x (HBx) protein is involved in the initiation and progression of HBV-related hepatocellular carcinoma (HCC) by regulating host protein-coding genes. However, the role of HBx in the epigenetic repression of miRNAs, which play important roles in gene regulation during hepatocarcinogenesis, remains largely unknown. In this study, the expression of miR-132 in HCC cells, HBV-related HCC tissues, and serum were determined using real-time PCR. The level of DNA methylation on the promoter of miR-132 was examined using methylation-specific PCR (MSP). MiR-132 was functionally characterized in HCC cells with transiently altered miR-132 expression. HBx-induced DNA hypermethylation of the promoter of miR-132 was found to be more prevalent in HBx-expressing HepG2 cells than in control cells. Consistently, MiR-132 expression was also more frequently down-regulated in HBV-related HCC tissues than in adjacent noncancerous hepatic tissues and had a significant inverse correlation with HBx expression in HBV-related HCCs. Serum miR-132 levels were found to be significantly correlated with levels in tumor tissue. Finally, proliferation and colony formation of HCC cells were found to be suppressed by miR-132-mediated inhibition of the Akt-signaling pathway in miR132 transfected cells. Our study has demonstrated the epigenetic repression of miR-132 expression through DNA methylation induced by HBx. This work provides novel mechanistic insights into HBV-mediated hepatocarcinogenesis and suggests that miR-132 may be a promising biochemical marker and may have therapeutic applications in HBV-related HCC.

Wei X ，Tan C ，Tang C ，Ren G ，Xiang T ，Qiu Z ，Liu R ，Wu Z ... -  《-》

miR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A.

The hepatitis B virus x (HBx) protein has been implicated in HBV-related hepatocellular carcinoma (HCC) pathogenesis. However, whether HBx regulates miRNA expression that plays important roles in gene regulation during hepatocarcinogenesis remains unknown. The expression of microRNA-101 (miR-101) in HBV-related HCC tissues and HCC cells was evaluated by real-time PCR. The direct target of miR-101, DNA methyltransferase 3A (DNMT3A), was identified in silico and validated using a 3'-UTR reporter assay. miR-101 was functionally characterized in cells with transiently altered miR-101 expression. HBx expression was found to have a significant inverse correlation with miR-101 expression in HBx-expressing HepG2 compared to control HepG2 cells. miR-101 expression was frequently down-regulated in HBV-related HCC tissues compared to adjacent noncancerous hepatic tissues and had a significant inverse correlation with DNMT3A expression in HBV-related HCCs. Further characterization of miR-101 revealed that it negatively regulated DNA methylation partly through targeting DNMT3A. HBx-mediated miR-101 down-regulation and DNMT3A up-regulation supported the enhanced DNA methylation of several tumor-suppressor genes in HBx-expressing cells. Our studies demonstrating the deregulation of miR-101 expression by HBx may provide novel mechanistic insights into HBV-mediated hepatocarcinogenesis and identify a potential miRNA-based targeted approach for treating HBV-related HCC.

Wei X ，Xiang T ，Ren G ，Tan C ，Liu R ，Xu X ，Wu Z ... -  《-》

[Correlation between androgen receptor expression and hepatitis B virus X protein and its clinical significance in hepatocellular carcinoma].

Gu DH ，Zhu YZ ，Wang X ，Bai ZC ，Ping JL ，Chen Q ，Zhu R ... -  《-》

Upregulated in Hepatitis B virus-associated hepatocellular carcinoma cells, miR-331-3p promotes proliferation of hepatocellular carcinoma cells by targeting ING5.

Cao Y ，Chen J ，Wang D ，Peng H ，Tan X ，Xiong D ，Huang A ，Tang H ... -  《Oncotarget》

MiR-19a, miR-122 and miR-223 are differentially regulated by hepatitis B virus X protein and involve in cell proliferation in hepatoma cells.

Yu G ，Chen X ，Chen S ，Ye W ，Hou K ，Liang M ... -  《Journal of Translational Medicine》