Interaction between endogeneous mutator AID and exogenous oncogenic factors in carcinogenesis

内源性突变 AID 与外源性致癌因子在致癌过程中的相互作用

• 批准号: 18390122
• 负责人: KINOSHITA Kazuo
• 金额: $ 10.77万
• 依托单位: Research Institute, Shiga Medical Center
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390122/
• 关键词: gene; cancer; genome; mutation

Activation-induced cytidine deaminase(AID) is a unique enzyme that can induce mutations in the genome and is an essential factor for somatic hypermutation and class-switch recombination of the immunoglobulin genes. This study revealed that AID was expressed not only in activated B lymphocytes but also in the liver under chronic hepatitis and tissues of hepatocellular carcinoma. AID expression in hepatocytes was upregulated by infection with hepatitis C virus. In the stomach, AID expression was induced in the epithelium by infection with Helicobacter pylori. AID expressed in a gastric cancer cell line could induce point mutations in a tumor suppressor p53 gene. These findings collectively suggested involvement of AID in the pathogenesis of epithelial cancer arising in the background of chronic inflammation and infection. To clarify role of AID in cancer, experiments of chemical-induced carcinogenesis were performed in mice. Initially, we used AID transgenic mice with ubiquitous and constitutive promoter, which were turned out to be unsuitable for the quantitative study because of frequent and early death from lethal lymphoma. The second trial using mice that lack lymphocytes failed due to growth retardation by frequent pneumonia. Therefore, we started the third trial generating a novel line of AID transgenic mice using skin-specific keratin 14 promoter. Obtained mice were backcrossed to FVB/N strain, which is prone to develop skin tumor. The skin tumor induction by chemicals has just begun.

激活诱导胞苷脱氨酶（AID）是一种独特的酶，可以诱导基因组突变，是体细胞超突变和免疫球蛋白基因类别转换重组的重要因素。这项研究表明，AID不仅在活化的B淋巴细胞中表达，而且在慢性肝炎下的肝脏和肝细胞癌组织中也表达。丙型肝炎病毒感染导致肝细胞中的AID表达上调。在胃中，幽门螺杆菌感染可在上皮细胞中诱导 AID 表达。胃癌细胞系中表达的 AID 可以诱导抑癌基因 p53 的点突变。这些发现共同表明 AID 参与了慢性炎症和感染背景下发生的上皮癌的发病机制。为了阐明 AID 在癌症中的作用，在小鼠中进行了化学诱导致癌实验。最初，我们使用具有普遍存在的组成型启动子的AID转基因小鼠，但由于致死性淋巴瘤频繁且早期死亡，这些小鼠被证明不适合定量研究。第二项试验使用缺乏淋巴细胞的小鼠，但由于频繁肺炎导致生长迟缓而失败。因此，我们开始了第三次试验，利用皮肤特异性角蛋白 14 启动子生成新的 AID 转基因小鼠品系。将获得的小鼠与易于发生皮肤肿瘤的FVB/N品系回交。化学物质诱导皮肤肿瘤才刚刚开始。

项目成果

Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis

• DOI: 10.1002/ijc.22292
• 发表时间: 2007-02-01
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Kou, Tadayuki;Marusawa, Hiroyuki;Chiba, Tsutomu
• 通讯作者: Chiba, Tsutomu

Hepatitis C virus triggers aberrant expression of actovaton-induced cytidine deaminase (AID) in human hepatocytes

丙型肝炎病毒触发人肝细胞中 Actovaton 诱导的胞苷脱氨酶 (AID) 的异常表达

• 发表时间: 2007
• 作者: 遠藤容子;他
• 通讯作者: 他

Identification of a specific domain required for dimerization of activation-induced cytidine deaminase

活化诱导胞苷脱氨酶二聚化所需的特定结构域的鉴定

• 发表时间: 2006
• 期刊: J. Biol. Chem. 281・28
• 作者: Wang;J. et al.
• 通讯作者: J. et al.

「研究成果報告書概要(和文)」より

摘自《研究结果报告摘要（日文）》

• 发表时间: 2005
• 作者: Kawauchi;et. al.;Nishimura et al.;Dezawa et al.;Yoshizawa et al.;星野 幹雄;星野 幹雄
• 通讯作者: 星野 幹雄

Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice

• DOI: 10.1073/pnas.0610732104
• 发表时间: 2007-01-30
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Kotani, Ai;Kakazu, Naoki;Honjo, Tasuku
• 通讯作者: Honjo, Tasuku