THE ROLES OF HEPATITIS C VIRUS AND INFLAMMATION IN THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA

丙型肝炎病毒感染后发生肝癌的机制尚不清楚。一种可能性是参与了氧化应激，氧化应激可以产生基因突变和严重的染色体变化，并有助于癌症的发展。我们最近发现，丙型肝炎病毒的核心蛋白在很长一段时间后，会在转基因小鼠中诱导肝细胞癌，并伴有明显的肝脏脂肪变性，但没有炎症反应，这表明丙型肝炎病毒直接参与了肝癌的发生。在16个月以上的老年核心基因转基因小鼠中，PCOOH水平增加了180%。同时，同一小鼠体内过氧化氢酶活性显著升高，总谷胱甘肽和还原型谷胱甘肽水平显著降低。有趣的是，酒精导致转基因小鼠体内PCOOH水平显著增加，这表明酒精和丙型肝炎病毒在肝癌发生中具有协同作用。因此，在没有…的情况下，丙型肝炎病毒核心蛋白在肝脏中处于氧化/抗氧化状态之后更多的炎症，从而可能有助于或促进，至少部分，在丙型肝炎病毒感染的肝细胞癌的发展。由于先前的研究表明ROS与丝裂原活化蛋白激酶(MAPK)密切相关，我们检测了短期酒精喂养的核心转基因和非转基因小鼠肝脏中c-jun氨基末端激酶、p38MAPK和细胞外信号调节激酶(ERK)的活性。与非转基因小鼠相比，核心转基因小鼠的ERK和p38MAPK活性增加，而正常饮食的核心转基因小鼠ERK和p38MAPK活性均未被激活。此外，p38MAPK和ERK下游通路--环磷酸腺苷和血清反应元件的活性也增加。通过基因芯片和实时定量聚合酶链式反应对基因表达谱的比较发现，在酒精喂养的核心转基因小鼠中，与细胞转化相关的Galectin-1显著增加。另一方面，在保护细胞免受氧化应激影响方面起关键作用的谷胱甘肽S转移酶减少。综上所述，这些结果表明，丙型肝炎病毒核心蛋白与乙醇协同激活一些MAPK通路，并导致多个基因的调控，从而在高酒精摄入量的丙型肝炎病毒感染患者的肝脏中观察到致病机制。较少

The mechanism of hepatocarcinogenesis in hepatitis C virus (HCV) infection is still undefined. One possibility is the involvement of oxidative stress, which can produce genetic mutations as well as gross chromosomal alterations and contribute to cancer development. We recently showed that the core protein of HCV induces, after a long period, hepatocellular carcinoma (HCC) in transgenic mice with marked hepatic steatosis but without inflammation, indicating a direct involvement of HCV in hepatocarcinogenesis. PCOOH level was increased by 180% in old core gene transgenic mice aged over 16 months. Concurrently, there was a significant increase in the catalase activity, and decreases in the levels of total and reduced glutathione in the same mice. Interestingly, alcohol caused a marked increase in PCOOH level in transgenic mice, suggesting synergism between alcohol and HCV in hepatocarcinogenesis. The HCV core protein thus afters the oxidant/antioxidant state in the liver in the absence of … More inflammation, and thereby may contribute to or facilitate, at least partly, the development of HCC in HCV infection. Since previous studies indicated that ROS is closely associated with mitogen-activated protein kinases (MAPK), we examined activities of c-Jun N-terminal kinase, p38 MAPK, and extracellular signal-regulated kinase (ERK) in the liver of core-transgenic and nontransgenic mice with short-term ethanol feeding. Activity of ERK and p38 MAPK was increased in core-transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated hi core-transgenic mice with normal diets. In addition, activity of cyclic-AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real-time PCR revealed that galectin-1, which is associated with cell transformation, was significantly increased in ethanol-fed core-transgenic mice. On the other hand, glutathione S-transferase, which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to pathogenesis observed in livers of HCV-infected patients with high ethanol consumption. Less