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

(l)HBV X蛋白具有多种功能。这些功能之一是调节细胞转录机制。研究表明，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，破坏线粒体膜的功能，导致细胞凋亡。(3)HCV编码几种蛋白质，其中一些显示出调节细胞增殖。其中，我们发现HCV核心蛋白对抗Fas抗体或TNF α诱导的细胞凋亡具有抗凋亡作用。(4)HCV蛋白还通过尚未阐明的机制激活Raf/Ras信号传导。(5)分析表达完整HCV蛋白的转基因小鼠的CTL活化，以阐明表达HCV蛋白的肝细胞持续存活的机制。该分析显示，树突状细胞的细胞表面上的MHC II类分子的水平降低，尽管蛋白质的产生没有改变。因此，这表明抗原呈递细胞对CTL的激活在该小鼠中被下调，这可能是慢性肝炎患者中CTL活性低的一种机制。(6)肝细胞癌组织常具有抗凋亡活性。为了阐明这种现象的机制，研究了BAD的磷酸化，BAD是细胞凋亡的调节因子。肝癌组织中BAD的磷酸化水平增强，提示BAD在肝癌细胞抗凋亡中起作用。

(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.