Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein-induced hepatocarcinogenesis.
Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein-induced hepatocarcinogenesis.
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Farnesoid X 受体消融使小鼠对乙型肝炎病毒 X 蛋白诱导的肝癌发生敏感
DOI：
10.1002/hep.28924
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Xie W
中科院分区：
文献类型：
--
作者：
Niu Y;Xu M;Slagle BL;Huang H;Li S;Guo GL;Shi G;Qin W;Xie W
慢性B型肝炎病毒（HBV）感染是肝细胞癌（HCC）的主要危险因素。B型肝炎病毒X蛋白（HBx）是一种具有多种细胞功能的HBV蛋白，但其在肝癌发病机制中的作用一直存在争议。法尼醇X受体（FXR）是一种具有抗炎和抑制肝癌发生作用的核受体。然而，FXR是否或如何影响HBV/HBx诱导的肝癌发生仍不清楚。在这项研究中，我们发现HBx可以与FXR相互作用，并作为FXR的共激活剂发挥作用。HBx在体内的表达增强了FXR应答基因的调节。荧光素酶报告基因检测显示HBx还能增强FXR的转录活性。通过免疫共沉淀和GST-下拉试验证实了HBx-FXR相互作用，并将FXR AF-1结构域定位为与HBx C-末端的第三个α螺旋结合。我们还发现，在临床HCC中发现的HBx的C-末端截短变体在反式激活FXR中无效。有趣的是，募集全长HBx，而不是C-末端截短的HBx，增强了FXR与其反应元件的结合。在体内，FXR消融显著地使小鼠对HBx诱导的肝癌发生敏感。我们认为全长HBx对FXR的反式激活可能是抑制HCC的一种保护性机制，并且这种抑制可能在C-末端截短的HBx出现时或当FXR的表达和/或活性降低时受到损害。
Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a HBV protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. The farnesoid X receptor (FXR) is a nuclear receptor known to have activities in anti-inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact HBV/HBx-induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a co-activator of FXR. Expression of HBx in vivo enhanced FXR responsive gene regulation. HBx also increased the transcriptional activity of FXR in luciferase reporter gene assay. The HBx-FXR interaction was confirmed by co-immunoprecipitation and GST-pull down assays, and the FXR AF-1 domain was mapped to bind to the third α helix in the C-terminal of HBx. We also found that the C-terminal truncated variants of HBx, which were found in clinical HCC, were not effective in transactivating FXR. Interestingly, recruitment of the full-length HBx, but not the C-terminal truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx-induced hepatocarcinogenesis. We propose that transactivation of FXR by the full-length HBx may represent a protective mechanism to inhibit HCC, and this inhibition may have been compromised upon the appearance of the C-terminal truncated HBx, or when the expression and/or activity of FXR is decreased.