Study on the mechanism of hepatocarcinogenesis in hepatitis C viral infection

丙型肝炎病毒感染致肝癌机制研究

• 批准号: 13214018
• 负责人: KOIKE Kazuhiko
• 金额: $ 25.15万
• 依托单位: The University of Tokyo
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13214018/
• 关键词: hepatitis C virus; hepatocarcinogenesis; transgenic mouse; core protein; oxidative stress; intracellular signal transduction; retinoid X receptor; insulin resistance; 肝細胞癌; ROS; MAPK; AP-1; β酸化; 脂肪化; DNA障害; アポリポ蛋白

Despite numerous lines of epidemiological evidence connecting hepatitis C virus (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 an oncogenic potential. HCV is directly involved in hepatocarcinogenesis, albeit other factors such as inflammation and environmental factors may also play a role. The direct involvement of HCV in hepatocarcinogenesis would be achieved via two 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 modulations of cellular gene expressions and intracellular signal transductions, such as mitogen-activated protein kinases (MAPKs) pathway, which results in the activation of transcription factors and cell cycle machineries. The combination of these alterations would 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, may 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, would explain the unusually high incidence and multicentric nature of HCC development in HCV infection.

尽管有大量的流行病学证据表明丙型肝炎病毒（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（MAPK）途径，它导致转录因子和细胞周期机制的激活。这些改变的组合将在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”致癌作用的情况可以解释HCV感染中HCC发展的异常高发病率和多中心性。

项目成果

Fujie H, Shintani Y, Miyoshi H, Moriya K. Hepatitis C and Diabetes Mellitus : what is the metabolic pathway?

Fujie H、Shintani Y、Miyoshi H、Moriya K。丙型肝炎和糖尿病：代谢途径是什么？

• 发表时间: 2004
• 期刊: Gastroenterology 127
• 作者: Shintani Y;Fujie H;Miyoshi H;Tsutsumi T;Kimura S;Moriya K;Koike K.;Koike K
• 通讯作者: Koike K

Miyamura T. Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice.

Miyamura T. 在转基因小鼠中，丙型肝炎病毒核心蛋白与乙醇协同激活 ERK 和 p38 MAPK。

• 发表时间: 2002
• 期刊: Hepatology 38
• 作者: Tsutsumi T;Suzuki T;Moriya K;Shintani Y;Fujie H;Miyoshi H;Matsuura Y;Koike K
• 通讯作者: Koike K

The role of hepatitis viruses in multistep hepatocarcinogenesis.

肝炎病毒在多步肝癌发生中的作用。

• 发表时间: 2001
• 期刊: Dig Liver Dis 33
• 作者: Moriya K;Todoroki T;Tsutsumi T;Fujie H;Shintani Y;Miyoshi H;Ishibashi K;Takayama T;Makuuchi M;Watanabe K;Miyamura T;Kimura S;Koike K.;Koike K.
• 通讯作者: Koike K.

Virological analysis of non-B, non-C hepatocellular carcinoma in Japan : frequent involvement of hepatitis B virus

日本非 B、非 C 型肝细胞癌的病毒学分析：乙型肝炎病毒频繁参与

• 发表时间: 2000
• 期刊: J Infect Dis 181
• 作者: Yotsuyanagi H;Shintani Y;Moriya K;Fujie H;Tsutsumi T;Kato T;Nishioka K;Takayama T;Makuuchi M;Iino S;Kimura S;Koike K.
• 通讯作者: Koike K.

Fujie H, et al.: "Frequent β-catenin aberration in human hepatocellular carcinoma"Hepatol Res. 20. 39-51 (2001)

Fujie H 等人：“人肝细胞癌中常见的 β-连环蛋白畸变”Hepatol Res. 20. 39-51 (2001)