Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis
Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis
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DOI：
10.1002/hep.20621
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发表时间：
2005-03-01
期刊：
影响因子：
13.5
通讯作者：
Chung, RT
中科院分区：
文献类型：
--
作者：
Kamegaya, Y;Hiasa, Y;Chung, RT
我们开发了丙型肝炎病毒（HCV）核心E1-E2和HCV核心转基因小鼠在一个共同的遗传背景，以评估HCV结构蛋白的贡献，肝癌发生。用二乙基亚硝胺（DEN）处理8周龄的核心-E1-E2、核心和非转基因小鼠（在FVB X C57 B1/6背景下近交），并在32周龄时处死。免疫组化法检测细胞增殖和凋亡。在抗Fas抗体诱导凋亡的HepG 2细胞中评价病毒蛋白对凋亡的影响。在32周时，在所有三组的大多数DEN治疗小鼠中鉴定出HCC。核心-E1-E2转基因小鼠HCC的平均大小（4.63 ± 1.48 mm）显著大于核心转基因小鼠（0.78 ± 0.26 mm，P = 0.01）和非转基因小鼠（1.0 ± 0.19 mm，P = 0.002）。虽然在增殖方面没有差异，但核心-E1-E2转基因HCC中的凋亡指数显著低于核心和非转基因HCC中发现的凋亡指数。Core-E1-E2转染的HepG 2细胞表现出显著较低的凋亡指数（0.35 +/- 0. 11)与核心转染细胞相比（0.74 ± 0.07，P = 0.0103）。在HCV转基因小鼠中Fas诱导的细胞凋亡模型的分析证实，核心-E1-E2转基因肝脏比仅表达核心的转基因组织经历显著更少的细胞凋亡。总之，HCV核心-E1-E2转基因小鼠比仅表达核心的转基因小鼠或非转基因小鼠产生显著更大的肿瘤。加速的肿瘤表型可归因于细胞凋亡的抑制而不是增殖的增强。这些数据表明HCV E1和/或E2与核心蛋白一起作为抗凋亡、肿瘤加速蛋白。
We developed hepatitis C virus (HCV) core-E1-E2 and HCV core transgenic mice on a common genetic background to assess the contribution of HCV structural proteins to hepatocarcinogenesis. Eight-week-old core-E1-E2, core, and nontransgenic mice inbred on the FVB X C57Bl/6 background were treated with diethylnitrosamine (DEN) and sacrificed at 32 weeks old. Proliferation and apoptosis were assessed by immunohistochemistry. The effect of viral proteins on apoptosis was evaluated in HepG2 cells in which apoptosis was induced by anti-Fas antibody. HCCs were identified at 32 weeks in the majority of DEN-treated mice from all three groups. The mean size of HCCs was significantly larger in core-E1-E2 transgenic (4.63 +/- 1.48 mm), compared with core transgenic (0.78 +/- 0.26 mm, P =.01), and nontransgenic (1.0 +/- 0.19 mm, P =.002) mice. While there were no differences in proliferation, the apoptotic index in core-E1-E2 transgenic HCCs was significantly lower than those found in core and non-transgenic HCCs. Core-E1-E2 transfected HepG2 cells demonstrated a significantly lower apoptotic index (0.35 +/- 0. 11) compared with that of core transfected cells (0.74 +/- 0.07, P =.0103). Analysis of a Fas-induced apoptosis model in HCV transgenic mice confirmed that core-E1-E2 transgenic liver underwent significantly less apoptosis than transgenic tissue expressing core only. In conclusion, HCV core-E1-E2 transgenic mice develop significantly larger tumors than transgenic mice expressing core alone or nontransgenic mice. The accelerated tumor phenotype is attributable to suppression of apoptosis rather than enhanced proliferation. These data implicate HCV E1 and/or E2 in conjunction with core as antiapoptotic, tumor accelerator proteins.