Hepatitis B virus X induces inflammation and cancer in mice liver through dysregulation of cytoskeletal remodeling and lipid metabolism.
Hepatitis B virus X induces inflammation and cancer in mice liver through dysregulation of cytoskeletal remodeling and lipid metabolism.
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乙型肝炎病毒 X 通过细胞骨架重塑和脂质代谢失调诱导小鼠肝脏炎症和癌症
DOI：
10.18632/oncotarget.12372
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Xu P
中科院分区：
文献类型：
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作者：
Xu Z;Zhai L;Yi T;Gao H;Fan F;Li Y;Wang Y;Li N;Xing X;Su N;Wu F;Chang L;Chen X;Dai E;Zhao C;Yang X;Cui C;Xu P
乙型肝炎病毒X蛋白（HBx）作为一种多功能调控因子参与肝细胞癌（HCC）的发生发展过程。然而，潜在的分子机制仍然不清楚。在这里，我们描述了使用p21HBx/+小鼠和SILAM（哺乳动物稳定同位素标记）策略来定义HBx诱导肝癌发生和发展的病理机制。我们系统地比较了一系列来自正常小鼠、12月龄和24月龄p21HBx/+小鼠的蛋白质组样本，这些小鼠分别代表肝脏疾病的炎症和HCC阶段，以及它们的非转基因野生型（WT）幼崽。在2473个定量蛋白中，共鉴定出22个和97个差异表达蛋白。生物信息学分析表明，脂质代谢和cdc42诱导的细胞骨架重塑途径被HBx转基因强烈激活。有趣的是，蛋白-蛋白相互作用MS研究显示，HBx在这两种途径中直接与多种蛋白相互作用。在转染HBx的Huh-7细胞中，也观察到细胞骨架和脂质代谢相关蛋白（包括CDC42、CFL1、PPARγ和ADFP）上调的同样效果。更重要的是，CFL1和ADFP在hbv相关性HCC （HBV-HCC）患者样本中特异性积累，其表达水平与hbv相关性肝病的严重程度呈正相关。这些结果为HBx诱导细胞骨架重塑和脂质代谢失调，导致肝癌发生发展提供了证据。CFL1和ADFP可能作为HBV-HCC预后和诊断的潜在生物标志物。
Hepatitis B virus X protein (HBx) participates in the occurrence and development processes of hepatocellular carcinoma (HCC) as a multifunctional regulation factor. However, the underlying molecular mechanism remains obscure. Here, we describe the use of p21HBx/+ mouse and SILAM (Stable Isotope Labeling in Mammals) strategy to define the pathological mechanisms for the occurrence and development of HBx induced liver cancer. We systematically compared a series of proteome samples from regular mice, 12- and 24-month old p21HBx/+ mice representing the inflammation and HCC stages of liver disease respectively and their nontransgenic wild-type (WT) littermates. Totally we identified 22 and 97 differentially expressed proteins out of a total of 2473 quantified proteins. Bioinformatics analysis suggested that the lipid metabolism and CDC42-induced cytoskeleton remodeling pathways were strongly activated by the HBx transgene. Interestingly, the protein-protein interaction MS study revealed that HBx directly interacted with multiple proteins in these two pathways. The same effect of up-regulation of cytoskeleton and lipid metabolism related proteins, including CDC42, CFL1, PPARγ and ADFP, was also observed in the Huh-7 cells transfected with HBx. More importantly, CFL1 and ADFP were specifically accumulated in HBV-associated HCC (HBV-HCC) patient samples, and their expression levels were positively correlated with the severity of HBV-related liver disease. These results provide evidence that HBx induces the dysregulation of cytoskeleton remodeling and lipid metabolism and leads to the occurrence and development of liver cancer. The CFL1 and ADFP might be served as potential biomarkers for prognosis and diagnosis of HBV-HCC.