HBV病毒感染和化学致癌物黄曲霉毒素AFB1暴露是我国原发性肝细胞癌(Hepatocellular Carcinoma, HCC)发生的两大主要危险因素，二者协同致HCC发生机制不清。我们前期发现，核受体PXR通路异常与HBV感染相关HCC发生有关；HBx是PXR的一个新Co-factor；HBx增加AFB1肝毒性呈PXR依赖模式；HBx以配体依赖和剂量依赖方式调控PXR转录活性及AFB1肝内代谢关键酶谱（AFB1代谢为AFBO及AFBO分解的关键酶）的表达；HBx knock in小鼠瞬时毒性和AFB1慢性诱瘤预实验证实AFB1肝内代谢与PXR通路激活相关。综上，本课题拟以sPXR-(HBx-PXR signaling)-AFB1代谢酶谱-（AFB1-DNA加合物）/TP53突变-HCC发生为主线，深入研究HCC中AFB1与HBV暴露的关系，以期揭示二者协同致HCC发生的分子机制。

Hepatitis B virus (HBV) infections and xenobiotics exposure are considered to be two major etiological factors for hepatocellular carcinoma (HCC) in China. Previous data has suggested a strong statistical interaction between HBV infection and Aflatoxin B1 (AFB1) exposure in etiology of HCC by epidemiological studies. However, molecular mechanism of the synergistic interaction in HCC was still poorly understood. We found that the ectopic models of Pregnane X receptor (PXR) signaling are associates with pathological progression in HBV infection associated liver diseases, and the expression level of PXR is high might be an early event in hepatocarcinogenesis. We further confirmed that HBx is a novel co-factor of PXR. In addition, HBx can significantly enhance the PXR transcriptional activity in the ligand and dose dependent manner, and the recruitment of HBx to the cytochrome P450-3A4 (CYP3A4) chromatin by PXR is in promoter dependent fashion. Notably, HBx-PXR signaling regulates the expression of key enzymes responsible for AFB1 metabolism of detoxification and carcinogenic activation, in PXR dependent manner. Especially in the presence of PXR agonist, HBx can significantly enhance the cytotoxicity of AFB1.So, the goal of this project is to investigate the link among sPXR (small PXR, a new truncated PXR isofrom)-(HBx-PXR signaling)-(AFB1 metabolizing enzymes)-(AFB1-DNA conjunction) or TP53 mutation-hepatocellular carcinogenesis in HBV infection associated hepatocarcinogenesis and to discover the mechanisms of synergistic effect of chemical and infectious carcinogens.