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Study of the molecular mechanism underlying genomic alterations during Helicobacter pylori-associated gastric carcinogenesis.

研究幽门螺杆菌相关胃癌发生过程中基因组改变的分子机制。

基本信息

批准号：
22890089
负责人：
MATSUMOTO Yuko
金额：
$ 2.19万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Research Activity Start-up
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

项目摘要

With persistent infection of Helicobacter pylori(H. pylori), gastric cancer develops by a multistep process occurring through the accumulation of genetic alterations in gastric epithelial cells. The mechanisms how the gastric epithelial cells with H. pylori infection and the resultant inflammatory response acquire the genetic changes leading to malignant transformation, however, remain unknown. Activation-induced cytidine deaminase(AID) induces somatic mutations in various host genes of non-lymphoid tissues, thereby contributing to carcinogenesis. Indeed, we demonstrated that H. pylori infection induced aberrant AID expression in gastric epithelial cells, resulting in the accumulation of p53 tumor suppressor gene mutations. Our findings suggested the novel link among H. pylori infection, accumulation of genetic changes and human gastric cancer development. The process of accumulation of genetic alterations induced by AID activity, however, have not yet been clarified.We plan to investigate the role of AID in the occurrence of genetic alterations, including somatic mutations and chromosomal changes. We clarify the overall genetic alterations induced by aberrant AID activity using the genome-wide array comparative genomic hybridization(CGH) analyses as well as the comprehensive mutation assays. The results are also assessed in mouse models with the oral challenge of H. pylori and in AID transgenic mice to investigate whether aberrant AID expression induced by H. pylori infection in vivo could contribute to the occurrence of tumor-promoting genetic changes, leading to the gastric cancer development. A successful outcome of this research project would provide the novel insight into the molecular mechanisms of infection-and inflammation-associated carcinogenesis.

幽门螺杆菌(H。幽门螺杆菌)，胃癌的发展是一个多步骤的过程，通过胃上皮细胞遗传改变的积累而发生。然而，幽门螺杆菌感染的胃上皮细胞以及由此产生的炎症反应如何获得导致恶性转化的遗传改变的机制尚不清楚。激活诱导胞苷脱氨酶（Activation-induced cytidine deaminase， AID）可诱导多种非淋巴组织宿主基因发生体细胞突变，从而促进癌变。事实上，我们证明了幽门螺杆菌感染诱导胃上皮细胞中AID的异常表达，导致p53肿瘤抑制基因突变的积累。我们的研究结果表明幽门螺杆菌感染、基因变化的积累和人类胃癌的发展之间存在新的联系。然而，由AID活性引起的遗传改变的积累过程尚未得到澄清。我们计划研究AID在遗传改变发生中的作用，包括体细胞突变和染色体改变。我们利用全基因组阵列比较基因组杂交（CGH）分析和综合突变分析阐明了由异常AID活性引起的总体遗传改变。我们还在口腔幽门螺杆菌攻毒小鼠模型和AID转基因小鼠模型中评估了这些结果，以研究体内幽门螺杆菌感染诱导的AID异常表达是否会导致促肿瘤基因改变的发生，从而导致胃癌的发生。该研究项目的成功成果将为研究感染和炎症相关癌变的分子机制提供新的见解。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nucleotide-binding Oligomerization Domain 1 Contributes to Host Defenseagainst Helicobacter pylori via Induction of Type I IFN and Activation of the IFN-stimulated Gene Factor 3 Signaling Pathway

核苷酸结合寡聚化结构域 1 通过诱导 I 型 IFN 和激活 IFN 刺激的基因因子 3 信号通路，有助于宿主防御幽门螺杆菌

DOI：
发表时间：
2010
期刊：
Journal of Clinical Investigation (In press)
影响因子：
0
作者：
Watanabe T;Asano N;Fichtner-F S;Gorelick P;Tsuji Y;Matsumoto Y;Chiba T;Fuss I;Kitani A;Strober W.
通讯作者：
Strober W.

Excessive activity of apolipoprotein B mRNA editing enzyme catalytic polypeptide 2 (APOBEC2) contributes to liver and lung tumorigenesis