Oxidative stress and hepatocarcinogenesis in hepatitis C

我们发现，丙型肝炎病毒核心蛋白诱导DNA氧化损伤，而它抑制细胞凋亡，并伴随着活性氧的增加。丙型肝炎病毒核心蛋白通过增加Bclxl蛋白和降低Bax蛋白来抑制细胞凋亡，从而抑制细胞色素c从线粒体释放到细胞质。然而，丙型肝炎病毒核心蛋白本身诱导的氧化应激程度似乎不足以导致肝细胞癌的发生。因此，我们把重点放在丙型肝炎中观察到的肝脏铁超载，作为放大氧化应激的第二次打击。我们建立了表达丙型肝炎病毒多聚蛋白的转基因小鼠，其肝脏铁浓度与慢性丙型肝炎患者相当。这些小鼠表现出明显的肝脏脂肪变性，包括小叶中心微泡类型，线粒体超微结构变化，脂肪酸降解活性降低，肝脏脂质过氧化产物和8-羟基-2‘-脱氧鸟苷含量增加。最后，45%的小鼠出现了包括肝细胞癌在内的肝脏肿瘤。这些结果表明，氧化应激和丙型肝炎病毒蛋白对细胞凋亡的调控是相互独立的，在表达丙型肝炎病毒多蛋白的转基因小鼠中，铁超载会导致线粒体损伤，增加肝癌发生的风险。

We have found that hepatitis C virus (HCV) core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of reactive oxygen species production. HCV core protein inhibited apoptosis by increasing Bcl-xL protein and decreasing Bax protein, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. However, magnitude of oxidative stress induced by HCV core protein itself seemed to be not enough for the development of hepatocellular carcinoma (HCC). We, therefore, focused on hepatic iron overload observed in hepatitis C as a second hit for amplifying oxidative stress. We established transgenic mice expressing the HCV polyprotein whose hepatic iron concentrations was comparable to those of patients with chronic hepatitis C. These mice showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alternations of the mitochondria, decreased degradation activity of fatty acid, and increased hepatic content of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine. Finally liver tumors including HCC developed in 45% of these mice. From these results, it has been shown that oxidative stress and apoptosis modulation by HCV protein are independent of each other, and that iron overload induces mitochondrial injury and increases the risk of HCC development in transgenic mice expressing the HCV polyprotein.