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Clarification of molecular mechanisims of hepatocellular carcinoma caused by hepatitis virus infection.

阐明肝炎病毒感染所致肝细胞癌的分子机制。

基本信息

批准号：
09253102
负责人：
SHIMOTOHNO Kunitada
金额：
$ 67.2万
依托单位：
Institute for Virus Research, Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

(l) HBV X protein has versatile functions. One of such the functions is to modulate cellular transcriptional machinary. It was shown that X protein associates with one of RNA polymerase binding protein and that X protein also competes with other cellular protein to interact with transcriptional machinary.(2) HBV X protein associates with mitochondrial membrane and disrupt the function of it. This disruption induces apoptosis. (3) HCV encode several proteins, some of which are shown to modulate cell proliferation. Among them we found that HCV core protein has anti-apoptotic function to cells induced by anti-Fas antibody or TNFa.(4) HCV protein also functions to activate Raf/Ras signaling by yet unclarified mechanism.(5) Trangenic mice expressing the entire HCV proteins was analyzed for their activation of CTL to clarify the mechanism of persistence of survival of HCV protein expressing hepatocytes. It was shown from this analysis that the level of MHC class II molecule on cell surface of dendritic cells was reduced although the production of the protein was not altered. Thus, it is suggested that activation of CTL by the antigen presenting cells is down regulated in this mouse and this may be one mechanism that the CTL activity in patients with chronic hepatitis is low.(6) Cancerous tissues of hepatocyte often have anti-apoptotic activity. To clarify the mechanism underling this phenomenon, phosphorylation of BAD, a regulator of apoptosis, was examined. Phosphorylation of BAD was enhanced in the cancerous portion, suggesting that BAD play a role in anti-apoptotic function of hepatoma cells.

(1) HBV X蛋白具有多种功能。其中一个功能是调节细胞的转录机制。结果表明，X蛋白与RNA聚合酶结合蛋白之一结合，并与其他细胞蛋白竞争与转录机制相互作用。(2) HBV X蛋白与线粒体膜结合，破坏线粒体膜功能。这种破坏诱导细胞凋亡。(3) HCV编码几种蛋白质，其中一些蛋白质被证明可以调节细胞增殖。其中我们发现HCV核心蛋白对抗fas抗体或TNFa诱导的细胞具有抗凋亡功能。(4) HCV蛋白也能激活Raf/Ras信号，但机制尚不清楚。(5)分析表达全HCV蛋白的转基因小鼠的CTL活化情况，阐明表达HCV蛋白的肝细胞持续存活的机制。分析结果表明，树突状细胞表面的MHCⅱ类分子水平降低，但蛋白的产生没有改变。因此，我们认为抗原提呈细胞对CTL的激活在该小鼠中被下调，这可能是慢性肝炎患者CTL活性低的机制之一。(6)肝细胞癌变组织常具有抗凋亡活性。为了阐明这一现象的机制，我们研究了BAD（细胞凋亡的调节因子）的磷酸化。BAD在癌变部分的磷酸化增强，提示BAD在肝癌细胞的抗凋亡功能中发挥作用。