Development of order-made medicine for gastric cancer prevention

根据各种流行病学研究，幽门螺杆菌与胃癌的发生有关。世界卫生组织国际癌症研究机构的一个工作组得出结论，幽门螺杆菌是人类的一类致癌物。将CagA阳性的幽门螺杆菌附着于胃上皮细胞后，由幽门螺杆菌通过4型分泌系统将CagA直接注射到细胞内，并在宿主细胞中进行酪氨酸磷酸化。最近，我们在胃上皮细胞中发现了CagA的靶蛋白。为src同源磷酸酶2 （SHP-2）。已知SHP-2在有丝分裂信号转导中发挥重要的积极作用，积极参与调节细胞的扩散、迁移和粘附。在本研究中，我们培育了cagA转基因小鼠。为了在小鼠胃中系统表达CagA， CagA分别连接到鸡β-肌动蛋白启动子和小鼠H^+ /K^+ - atp酶β-亚基基因启动子的下游。到72周龄时，8.3%的转基因小鼠出现了胃肠道息肉，1.8%的小鼠出现了胃肠道癌症。此外，一些使用鸡fl-actin启动子的转基因小鼠出现了白血病。这些发现提示CagA-SHP-2通路在幽门螺杆菌感染引起的癌变中起重要作用。

H.pylori has been implicated in gastric carcinogenesis on the basis of various epidemiological studies. A working group of the WHO International Agency for Research on Cancer concluded that H. pylori is a group I carcinogen in human. After attachment of cagA-positive H. pylori to gastric epithelial cells, CagA is directly injected from the H. pylori into the cells via the type 4 secretion system and undergoes tyrosine phosphorylation in the host cells. Recently, we found the target protein of CagA in the gastric epithelial cells. It was src homology phosphatase 2 (SHP-2). SHP-2 is known to play an important positive role in the mitogenic signal transduction that is actively involved in the regulation of spreading, migration, and adhesion of cells. In this study, we developed cagA transgenic mice. To express CagA systemically and predominantly in the stomach in mice, cagA was connected downstream of the chicken β-actin promoter and the β-subunit gene promoter of mouse H^+ /K^+ -ATPase, respectively. By 72 weeks of age, 8.3% of the transgenic mice developed gastrointestinal polyps, and 1.8% of the mice developed gastrointestinal cancers. In addition, some transgenic mice using the chicken fl-actin promoter developed leukemia.These findings suggest that CagA-SHP-2 pathway is important for carcinogenesis caused by H. pylori infection.