Hepatitis B virus X (HBx) play an anti-apoptosis role in hepatic progenitor cells by activating Wnt/β-catenin pathway
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Increasing evidence has shown that normal stem cells may act as cancer-initiating cells and contribute to the development and progression of cancer. HBx has a close relationship with hepatocellular carcinoma, however, the role of HBx in hepatic progenitor cells (HPCs) is poorly understood. In this study, we sought to determine the role of HBx in regulating HPCs apoptosis and the underlying molecular mechanism(s) using HPCs derived from mouse fetal liver. The apoptotic ratio of HPCs infected with adenovirus-expressing HBx (Ad-HBx) was examined using flow cytometry. Results showed that the Ad-HBx treatment led to substantially decreased apoptotic ratio of HPCs, as confirmed by the Hoechst 33342 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). Possible alterations of relative proteins were examined using Western blot and real-time PCR assays. The HBx expression in HPCs increased the expression levels of Bcl2 and Mcl1 while decreasing the expression levels of Bax and cleaved caspase-9 and -3. In addition, the mRNA and protein expression levels of β-catenin were both increased. The β-catenin protein were mainly accumulated in cytoplasm and tended to transfer into cell nucleus after Ad-HBx treatment. The over-expression of β-catenin decreased the apoptotic ratio of HPCs and inhibited the expression of cleaved caspase-9 and -3 while blocking β-catenin expression resulted in the opposite results. Taken together, our results strongly suggested that the HBx protein may inhibits apoptosis of hepatic progenitor cells, at least in part by activating the WNT/β-catenin pathway. This provided a new insight into the molecular mechanism of HBx-mediated live carcinogenesis.
KeywordsHepatitis B virus X Hepatic progenitor cells Apoptosis WNT/β-catenin pathway Cancer stem cells
We thank Dr. T. -C. He of The University of Chicago Medical Center for providing the cell lines, vectors and technical support. The reported work was supported by Research Grants from the Natural Science Foundation of China (Grant# 81071770, TF and Grant# 81201679, J Y H) .
Conflict of interest
The authors report no conflicts of interest.
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