Oxidative stress and hepatocarcinogenesis in hepatitis C

丙型肝炎的氧化应激和肝癌发生

• 批准号: 15590653
• 负责人: HINO Keisuke
• 金额: $ 2.37万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590653/
• 关键词: hepatitis C; hepatocarcinogenesis; oxidative stress; mitochondria; apoptosis; iron; animal model; HCV; トランスジェニックマウス; Bcl2ファミリー

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.

我们已经发现，丙型肝炎病毒（HCV）的核心蛋白诱导氧化DNA损伤，而它抑制细胞凋亡，伴随着活性氧产生的增强。HCV核心蛋白通过增加Bcl-xL蛋白和减少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中。然而，由HCV核心蛋白本身诱导的氧化应激的大小似乎不足以促进肝细胞癌（HCC）的发生。因此，我们将重点放在丙型肝炎中观察到的肝脏铁过载作为放大氧化应激的第二次打击。我们建立了表达HCV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脂肪变性，包括小叶中心微泡型，线粒体超微结构改变，脂肪酸降解活性降低，脂质过氧化产物和8-羟基-2 '-脱氧鸟苷含量增加。最后，这些小鼠中有45%发生了肝肿瘤，包括HCC。从这些结果，它已被证明，由HCV蛋白的氧化应激和细胞凋亡调节是相互独立的，铁过载诱导线粒体损伤和增加的风险HCC发展的转基因小鼠表达的HCV多蛋白。

项目成果

Hepatitis B virus genotype G is an extremely rare genotype in Japan

• DOI: 10.1016/j.hepres.2004.09.004
• 发表时间: 2004-12-01
• 期刊: HEPATOLOGY RESEARCH
• 影响因子: 4.2
• 作者: Kato, H;Sugauchi, F;Mizokami, M
• 通讯作者: Mizokami, M

Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species

• DOI: 10.1007/s00535-005-1738-1
• 发表时间: 2006-03-01
• 期刊: JOURNAL OF GASTROENTEROLOGY
• 影响因子: 6.3
• 作者: Hara, Y;Hino, K;Okita, K
• 通讯作者: Okita, K

Ren F: "Cytokine-dependent anti-viral role of CD-4 positive T cells in therapeutic vaccination against chronic hepatitis B viral infection"J Med Virol. 71. 376-384 (2003)

任峰：“CD-4阳性T细胞在慢性乙型肝炎病毒感染治疗性疫苗接种中的细胞因子依赖性抗病毒作用”J Med Virol。

Distinct geographic distributions of hepatitis B virus genotypes in patients with acute infection in Japan.

日本急性感染患者乙型肝炎病毒基因型的独特地理分布。

• 发表时间: 2005
• 期刊: J Med Virol 77
• 作者: Murakami Y;Hara Y;Hino K;Furutani T;Murakami Y.;Hara Y.;Hino K.;Furutani T.;Kitase A;Kitase A.;Kirase A;Yotsuyanagi H
• 通讯作者: Yotsuyanagi H

Interferon therapy for aged patients with chronic hepatitis C: improved survival in patients exhibiting a biochemical response

• DOI: 10.1007/s00535-004-1448-0
• 发表时间: 2004-11
• 期刊: Journal of Gastroenterology
• 影响因子: 6.3
• 作者: Y. Imai;A. Kasahara;Hideo Tanaka;T. Okanoue;N. Hiramatsu;H. Tsubouchi;K. Yoshioka;S. Kawata;E. Tanaka;K. Hino;K. Hayashi;S. Tamura;Y. Itoh;Y. Sasaki;K. Kiyosawa;S. Kakumu;K. Okita;N. Hayashi