Molecular mechanism for the development of gastric lesions by Helicobacter pylori infection

携带cagA基因的幽门螺杆菌（H. pylori）菌株比cagA阴性菌株毒性更强，并且与胃腺癌的发展有关。cagA基因产物cagA易位到胃上皮细胞中，定位于质膜的内表面，在EPIYA基序处发生酪氨酸磷酸化。酪氨酸磷酸化的CagA特异性结合并激活SHP-2酪氨酸磷酸酶和c端Src激酶（Csk），从而诱导被称为蜂鸟表型的细长细胞形状。东亚国家分离的hpylori CagA种比西方国家分离的hpylori具有更强的SHP-2结合活性和更高的病理生物学活性。因此，感染东亚caga阳性幽门螺杆菌的人群患胃癌的风险可能高于感染西方caga阳性或caga阴性菌株的人群。K-ras基因的功能获得性突变是人类肿瘤中最常见的基因变化之一。在携带K-ras突变的肿瘤中，致癌K-ras的存在不仅是肿瘤发生所必需的，也是维持转化表型所必需的。ESXR1是一种人类配对样同源结构域蛋白。全长ESXR1蛋白被蛋白水解加工成含有同源结构域和c端片段的n端片段。全长ESXR1和c端片段定位于细胞质，而含有n端同源结构域的ESXR1片段仅定位于细胞核内。n端ESXR1片段通过结合人类K-ras基因第一个内含子内的TAATGTTATTA序列抑制K-ras mRNA转录。在携带突变K-ras的人癌细胞中，n端ESXR1片段的表达降低了K-ras的水平，抑制了肿瘤细胞的增殖。ESXR1作为K-ras基因的转录抑制因子的鉴定对于开发针对致癌K-ras的癌症治疗具有重要意义。少

Helicobacter pylori (H. pylori) strains carrying the cagA gene are more virulent than cagA-negative strains and are associated with the development of gastric adenocarcinoma. The cagA gene product, CagA, is translocated into gastric epithelial cells and localizes to the inner surface of the plasma membrane, where it undergoes tyrosine phosphorylation at the EPIYA motifs. Tyrosine-phosphorylated CagA specifically binds and activates SHP-2 tyrosine phosphatase and the C-terminal Src kinase (Csk), thereby inducing an elongated cell shape termed the hummingbird phenotype. CagA species of H.pylori isolated in East Asian countries exhibit stronger SHP-2 binding activity and greater pathobiological activity than those isolated in Western countries. Thus, populations infected with East Asian cagA-positive H.pylori may be at greater risk for gastric cancer than those infected with Western cagA-positive or cagA-negative strains.Gain-of-function mutation of the K-ras gene is one of the most commo … More n genetic changes in human tumors. In tumors carrying K-ras mutation, the presence of oncogenic K-Ras is not only essential for the tumorigenesis but also necessary for maintenance of the transformed phenotype. ESXR1 is a human paired-like homeodomain-containing protein. The full-length ESXR1 protein is proteolytically processed into an N-terminal fragment containing the homeodomain and a C-terminal fragment. The full-length ESXR1 and the C-terminal fragment are localized to the cytoplasm, whereas the N-terminal homeodomain-containing ESXR1 fragment is exclusively localized within the nucleus. The N-terminal ESXR1 fragment represses K-ras mRNA transcription by binding to the TAATGTTATTA sequence present within the first intron of the human K-ras gene. Expression of the N-terminal ESXR1 fragment in human carcinoma cells that carry mutated K-ras reduces the level of K-Ras and inhibits the tumor cell proliferation. Identification of ESXR1 as a transcriptional repressor of the K-ras gene has an important implication for the development of cancer therapy that targets oncogenic K-ras. Less