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

幽门螺杆菌（Helicobacter pylori，H. pylori），胃癌通过胃上皮细胞中遗传改变的积累而发生的多步骤过程发展。本文对H.然而，幽门螺杆菌感染和由此产生的炎症反应获得导致恶性转化的遗传变化仍然是未知的。激活诱导的胞苷脱氨酶（AID）诱导非淋巴组织的各种宿主基因的体细胞突变，从而促进癌的发生。事实上，我们证明了H。pylori感染诱导胃上皮细胞AID表达异常，导致p53抑癌基因突变的积累。我们的研究结果表明，H。pylori感染、基因改变的积累与人胃癌的发生。然而，由AID活性诱导的遗传改变的积累过程尚未阐明，我们计划调查AID在遗传改变的发生中的作用，包括体细胞突变和染色体变化。我们阐明了整体的遗传变异异常AID活动诱导使用全基因组阵列比较基因组杂交（CGH）分析，以及全面的突变检测。结果也在口服H. pylori感染和AID转基因小鼠，研究H.体内pylori感染可导致促肿瘤基因改变的发生，从而导致胃癌的发生。该研究项目的成功结果将为感染和炎症相关致癌的分子机制提供新的见解。

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.