Improving Hepatocellular Carcinoma Chemotherapy by Silencing Hepatitis B Virus X Target Genes

The cellular functions ascribed to hepatitis B virus X (HBx) are unusually diverse, including modulation of transcription, signal transduction, cell cycle progress, protein degradation pathways, apoptosis, and genetic stability by directly or indirectly interacting with host factors. HBx has been long suspected to be involved in hepatocarcinogenesis, especially hepatocellular carcinoma (HCC), although its oncogenic role remains controversial. Interaction of HBx with cellular key proteins such as p53, p21 and PTEN marks this viral protein important in the control of cell growth and death (apoptosis). Interestingly, HCCs are relatively resistant to chemotherapy. By assumimg that HBx mediates the chemoresistance in HCC, we recently found that the HBx level and its target genes is critical in the impact on cell response to chemotherapy. At present state, we hypothesize that cell response to chemotherapy can be regulated by the HBx targets in cells especially gene products involved in regulating apoptosis. To examine this hypothesis, the following questions are asked: 1) Find HBx upregulated genes that cause chemoresistance, 2) Find mechanism of the HBx-regulated chemoresistance, and 3) overcome chemoresistance of HCC by synthetic therapy with silencing the HBx target genes and anticancer drugs. Identification and verification of the candidate genes will be performed in cell-based models, followed by in vivo assay of xenograft growth in mouse models and clinical correlation. Preliminary data suggest at least three HBx-upregulated, chemoresistance genes (RHAMM, URG11, HURP) for further investigation in vitro and in vivo. Our results will shed light on the understanding of how HBx affect cell growth/death and how HCC is developed in chronic HBV infection. Importantly, our findings may also provide foundation for the development of effective novel therapy.

Project ID:PC10008-0919
External Project ID:NSC100-2321-B182-007