A Zebrafish Model of Intrahepatic Cholangiocarcinoma by Dual Expression of Hepatitis B Virus X and Hepatitis C Virus Core Protein in Liver
A Zebrafish Model of Intrahepatic Cholangiocarcinoma by Dual Expression of Hepatitis B Virus X and Hepatitis C Virus Core Protein in Liver
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DOI：
10.1002/hep.25914
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发表时间：
2012-12-01
期刊：
影响因子：
13.5
通讯作者：
Wu, Jen-Leih
中科院分区：
文献类型：
--
作者：
Liu, Wangta;Chen, Jim-Ray;Wu, Jen-Leih
介导与乙型和丙型肝炎病毒（分别为HBV和HCV）感染相关的肝内胆管癌（ICC）的发生和发展的机制在很大程度上仍不清楚。在这项研究中，我们在斑马鱼肝脏中有条件地共表达乙型肝炎病毒X （HBx）和丙型肝炎病毒核心（HCP）蛋白，这导致3个月大的斑马鱼肝脏纤维化，从而导致ICC的形成。多西环素（Dox）处理抑制转基因表达导致ICC形成丧失。通过转录组测序和分析鉴定的斑马鱼ICC生物标志物网络也经常参与人类肿瘤的发展。斑马鱼ICC的潜在生物标志物基因谱与人类胆管癌相似。我们的数据还显示，pSmad3L致癌途径在HBx和hcp诱导的ICC中被激活，包括p38丝裂原活化蛋白基（MAPK）和p44/42丝裂原活化蛋白激酶（ERK1/2）的磷酸化，表明其与ICC中转化生长因子β 1 （tgf - β 1）信号通路相关。体内注射morpholinos敲低tgf - β 1可显著减少胆管增殖、纤维化和ICC。结论：这些结果表明tgf - β 1在hbx和hcp诱导的ICC发展中起重要作用。这种体内模型是研究HBV和HCV感染中发生的纤维化和ICC分子事件的潜在方法。(肝脏病学56:2268 2012;2276)
The mechanisms that mediate the initiation and development of intrahepatic cholangiocarcinoma (ICC) associated with hepatitis B and C virus (HBV and HCV, respectively) infection remain largely unclear. In this study we conditionally coexpressed hepatitis B virus X (HBx) and hepatitis C virus core (HCP) proteins in zebrafish livers, which caused fibrosis and consequently contributed to ICC formation at the age of 3 months. Suppressing the transgene expression by doxycycline (Dox) treatment resulted in the loss of ICC formation. The biomarker networks of zebrafish ICC identified by transcriptome sequencing and analysis were also frequently involved in the development of human neoplasms. The profiles of potential biomarker genes of zebrafish ICC were similar to those of human cholangiocarcinoma. Our data also showed that the pSmad3L oncogenic pathway was activated in HBx and HCP-induced ICC and included phosphorylation of p38 mitogen-activated proteinbase (MAPK) and p44/42 mitogen-activated protein kinase (ERK1/2), indicating the association with transforming growth factor beta 1 (TGF-beta 1) signaling pathway in ICC. Bile duct proliferation, fibrosis, and ICC were markedly reduced by knockdown of TGF-beta 1 by in vivo morpholinos injections. Conclusion: These results reveal that TGF-beta 1 plays an important role in HBx-and HCP-induced ICC development. This in vivo model is a potential approach to study the molecular events of fibrosis and ICC occurring in HBV and HCV infection. (HEPATOLOGY 2012;56:2268-2276)