Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis.
Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis.
复制标题
乙型肝炎病毒X蛋白与孕烷X受体相互作用增强黄曲霉毒素B1和乙型肝炎病毒促进肝癌发生的协同作用
DOI：
10.14218/jcth.2021.00036
复制
发表时间：
2021-08-28
影响因子：
3.6
通讯作者：
Shi G
中科院分区：
文献类型：
--
作者：
Niu Y;Fan S;Luo Q;Chen L;Huang D;Chang W;Qin W;Shi G
背景和目的已发现B型肝炎病毒（HBV）感染可通过未知的机制增加肝细胞对致癌性外源性物质的敏感性，从而导致肝细胞癌的发生。PXR是机体防御外源性物质的关键调节因子，包括外源性致癌物和临床药物。在这项研究中，我们的目的是探讨HBV X蛋白（HBx）-PXR信号转导的化学致癌物在HBV相关肝癌的协同作用的分子机制。方法采用PCR、Western blotting和组织芯片技术检测PXR-细胞色素p450 3A 4（CYP 3A 4）信号通路的表达。细胞活力和黄曲霉毒素B1（AFB 1）的细胞毒性使用细胞计数试剂盒-8测定。采用瞬时转染和真实的时间PCR评价靶基因表达。用新生小鼠单次注射黄曲霉毒素B1，评价其遗传毒性。结果HBx通过激活细胞色素P450 3A 4和还原谷胱甘肽S转移酶Mu 1（GSTM 1）增强AFB 1的肝毒性。在HBx转基因模型中，通过上调致癌KRAS以增强白细胞介素（IL）-11：IL-11受体亚单位α-1（IL 11 RA-1）介导的炎症，由双烯醇酮16α-腈激活PXR可增加AFB 1诱导的肝癌发病率。结论HBx-PXR-CYP 3A 4/GSTM 1-KRAS-IL 11：IL 11 RA信号轴增强AFB 1毒性的研究结果为化学致癌物在HBV感染相关肝癌发生中的协同作用提供了合理的解释。
Background and Aims Hepatitis B virus (HBV) infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics, by unknown mechanisms, in the generation of hepatocellular carcinoma. The pregnane X receptor (PXR) is a key regulator of the body’s defense against xenobiotics, including xenobiotic carcinogens and clinical drugs. In this study, we aimed to investigate the molecular mechanisms of HBV X protein (HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis. Methods The expression profile of PXR-cytochrome p450 3A4 (CYP3A4) signaling was determined by PCR, western blotting, and tissue microarray. Cell viability and aflatoxin B1 (AFB1) cytotoxicity were measured using the cell counting kit-8 assay. Target gene expression was evaluated using transient transfection and real time-PCR. The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1. Results HBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin (IL)-11:IL-11 receptor subunit alpha-1 (IL11RA-1)-mediated inflammation in an HBx transgenic model. Conclusions Our finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/ GSTM1-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.