Hepatitis B virus X protein boosts hepatocellular carcinoma progression by downregulating microRNA-137.

BACKGROUND:Hepatocellular carcinoma (HCC) is a frequent diagnosed malignancy. microRNAs (miRs) are involved in various cellular processes during cancer development. This study attempted to probe the miR-based mechanism in hepatitis B virus X protein (HBx) small interfering RNA (siRNA)-treated HCC cells. METHODS:HBx expression in hepatocyte and HCC cells was detected, and cells with highest HBx expression were screened out and transfected with HBx-siRNAs. Then the effect of HBx on HCC cell proliferation was detected. miRs differentially expressed in HBx-siRNA-transfected MHCC97H cells were analyzed and verified. miR-137 methylation was analyzed by bioinformatics, and miR-137 restoration was detected after Aza treatment. Furthermore, miR-137 methylation in MHCC97H cells with HBx knockdown or HBx overexpression was detected by methylation specific PCR. The targeting relationship between miR-137 and Notch1 was verified. Then the gain-and-loss functions of miR-137 or/and Notch1 were performed to estimate their roles in HCC cell proliferation. The effects of HBx-siRNA and overexpressed miR-137 in vivo were observed by tumor xenograft in nude mice and immunohistochemistry. RESULTS:HBx-siRNA weakened MHCC97H cell proliferation and tumor growth. miR-137 was highly expressed in HBx-siRNA-treated HCC cells and targeted Notch1. HBx knockdown decreased miR-137 methylation and restored miR-137 expression. miR-137 overexpression prevented HCC cell proliferation and tumor growth, while miR-137 downregulation reversed the repressing effects of HBx-siRNA on HCC cell proliferation. Inhibition of Notch1 reversed HCC cell proliferation induced by miR-137 downregulation. CONCLUSION:Overexpression of miR-137 blocks HCC cell proliferation in HBx-siRNA-treated MHCC97H cells by targeting Notch1. This study may offer novel target for HCC treatment.

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