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Analysis of risk factors for gastric cancer in order to construct tailor-made medicine for gastric cancer

分析胃癌危险因素构建胃癌个体化药物

基本信息

批准号：
15390231
负责人：
AZUMA Takeshi
金额：
$ 7.94万
依托单位：
University of Fukui (2004)福井医科大学 (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390231/
关键词：
H.pylori CagA Gastric cancer オーダーメイド医療

项目摘要

After attachment of cagA-positive H. pylori to gastric epithelial cells, CagA is directly injected from the bacteria into the cells via the bacterial type IV secretion system and undergoes tyrosine phosphorylation in the host cells. We recently discovered that translocated CagA forms a physical complex with SHP-2. SHP-2 is known to play an important positive role in mitogenic signal transduction. Deregulation of SHP-2 by CagA may induce abnormal proliferation of gastric epithelial cells. In addition, the CagA protein is polymorphic. We discovered that predominant CagA proteins isolated in East Asia, where gastric cancer is prevalent, have a distinct sequence at the phosphorylation site of CagA. East Asian-specific sequence confers stronger SHP-2 binding and transforming activities to Western CagA. The diversity of the CagA phosphorylation site, which collectively determines binding affinity of CagA to SHP-2, may be an important variable in determining the clinical outcome of infection. We examined the CagA diversity of H. pylori isolated from patients with chronic gastritis or gastric cancer in Japan. The prevalence of East Asian CagA was significantly higher in patients with gastric cancer than in patients with chronic gastritis. The risk for gastric cancer associated with East Asian CagA-positive H. pylori infection was 11.8 (95% confidence limits, 7.33 to 383.31). Endemic circulation of H. pylori populations with more virulent East Asian CagA proteins may affect the prevalence of gastric cancer.

cagA阳性H.在幽门螺杆菌至胃上皮细胞的过程中，CagA通过细菌IV型分泌系统从细菌直接注射到细胞中，并在宿主细胞中经历酪氨酸磷酸化。我们最近发现易位的CagA与SHP-2形成物理复合物。已知SHP-2在促有丝分裂信号转导中起重要的正性作用。CagA对SHP-2的调节失调可能导致胃上皮细胞异常增殖。此外，CagA蛋白是多态性的。我们发现，在胃癌流行的东亚分离的主要CagA蛋白在CagA的磷酸化位点具有不同的序列。东亚特异性序列赋予更强的SHP-2结合和转化活性的Western CagA。CagA磷酸化位点的多样性共同决定了CagA与SHP-2的结合亲和力，可能是决定感染临床结果的重要变量。我们检测了H.日本慢性胃炎或胃癌患者分离的幽门螺杆菌。东亚CagA在胃癌患者中的患病率显著高于慢性胃炎患者。东亚CagA阳性H. pylori感染率为11.8（95%可信限为7.33 ~ 383.31）。H. pylori人群中东亚人CagA蛋白毒性更强可能影响胃癌的患病率。