Molecular basis of hepatitis C virus-associated hepatocarcinogenesis: lessons from animal model studies.
Molecular basis of hepatitis C virus-associated hepatocarcinogenesis: lessons from animal model studies.
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DOI：
10.1016/s1542-3565(05)00700-7
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发表时间：
2005-10-01
期刊：
影响因子：
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通讯作者：
Koike, Kazuhiko
中科院分区：
文献类型：
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作者：
Koike, Kazuhiko
尽管有许多流行病学证据表明HCV感染与肝细胞癌（HCC）的发生有关，但HCV本身是否在HCC的发病机制中起直接或间接作用仍存在争议。通过使用转基因小鼠，已经证明HCV的核心蛋白具有致癌潜力。HCV直接参与肝癌发生，尽管其他因素如炎症和环境因素也可能发挥作用。HCV直接参与肝癌的发生可能通过两条途径实现。在一个途径中，核心蛋白作用于线粒体的功能，导致氧化应激的过度产生，从而在细胞生长相关基因中产生遗传畸变。另一条途径涉及细胞基因表达和细胞内信号转导的调节，如丝裂原活化蛋白激酶途径，其导致转录因子和细胞周期机制的激活。这些改变的组合将被假设为在HCV感染中引起HCC的发展。这可能是HCV感染中HCC发展的一种机制，与其他癌症不同。丙型肝炎病毒核心蛋白的存在，其中一个致癌的潜力，可能会允许一些多个步骤绕过肝癌。因此，与其他癌症不同的是，HCV感染可以在缺乏一套完整的遗传畸变的情况下引发HCC。这种“非Vogelstein型”的致癌作用可能解释了HCV感染中HCC发展的异常高发病率和多中心性。
Despite numerous lines of epidemiologic evidence connecting HCV infection and the development of hepatocellular carcinoma (HCC), it remains controversial whether HCV itself plays a direct role or an indirect role in the pathogenesis of HCC. Through the use of transgenic mice, it has become evident that the core protein of HCV has oncogenic potential. HCV is directly involved in hepatocarcinogenesis, albeit other factors such as inflammation and environmental factors might also play a role. The direct involvement of HCV in hepatocarcinogenesis would be achieved via 2 pathways. In one pathway, the core protein acts on the function of mitochondria, leading to the overproduction of oxidative stress, which yields genetic aberrations in cell growth-related genes. The other pathway involves the modulation of cellular gene expressions and intracellular signal transductions, such as mitogen-activated protein kinase pathway, which results in the activation of transcription factors and cell cycle machineries. The combination of these alterations would be hypothesized to provoke the development of HCC in HCV infection. This would be a mechanism for HCC development in HCV infection that is distinct from those for other cancers. The presence of the HCV core protein, to which an oncogenic potential is ascribed, might allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore, unlike in other cancers, HCV infection can elicit HCC in the absence of a complete set of genetic aberrations. Such a scenario, "non-Vogelstein type" carcinogenesis, may explain the unusually high incidence and multicentric nature of HCC development in HCV infection.