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

在cagA阳性的幽门螺杆菌附着在胃上皮细胞上后，cagA通过细菌IV型分泌系统直接从细菌注射到细胞内，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形成了物理复合体。SHP-2在促有丝分裂信号转导中发挥着重要的积极作用。CagA对SHP-2的失控可能会导致胃上皮细胞的异常增殖。此外，CagA蛋白是多态的。我们发现，在胃癌高发的东亚地区分离的主要CagA蛋白在CagA的磷酸化位点上有一个独特的序列。东亚特异序列对Western CagA具有较强的SHP-2结合和转化活性。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，这可能是决定感染临床结局的一个重要变量。我们检测了从日本慢性胃炎或胃癌患者中分离的幽门螺杆菌的CagA多样性。东亚CagA在胃癌患者中的患病率显著高于慢性胃炎患者。与东亚CagA阳性幽门螺杆菌感染相关的胃癌风险为11.8(95%可信限，7.33至383.31)。东亚CagA蛋白毒力较强的幽门螺杆菌种群的地方性循环可能影响胃癌的流行。

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.