Regulation of gastric carcinogenesis by helicobacter pylori virulence factors
Regulation of gastric carcinogenesis by helicobacter pylori virulence factors
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DOI：
10.1158/0008-5472.can-07-0824
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发表时间：
2008-01-15
期刊：
影响因子：
11.2
通讯作者：
Peek, Richard M., Jr.
中科院分区：
文献类型：
--
作者：
Franco, Aime T.;Johnston, Elizabeth;Peek, Richard M., Jr.
幽门螺杆菌是已知的胃腺癌最强的危险因素，并且具有cag分泌系统的菌株，其将细菌效应物CagA易位到宿主细胞中，增加癌症风险。H.表达空泡化细胞毒素或外膜蛋白OipA的幽门螺杆菌菌株与严重的病理结果相似。我们以前报道，在体内适应H。pylori菌株7.13在胃炎的啮齿动物模型中诱导胃腺癌。在本研究中，我们使用致癌菌株7.13作为原型，以确定毒力成分在H。幽门介导的致癌作用蒙古沙鼠感染野生型菌株7.13或cagA（-）、vacA（-）或oipA（-）突变体12至52周。所有感染的沙鼠都出现胃炎;然而，在感染cagA（-）而不是vacA（-）或oipA（-）菌株的动物中，炎症显著减弱。在感染野生型或vacA-菌株的沙鼠中，>50%的沙鼠发生胃发育不良和癌症，但在感染cagA（-）菌株的动物中没有发生。oipA的失活降低了体外β-连环蛋白的核定位，并降低了沙鼠的癌症发病率。OipA的表达在H.幽门螺杆菌菌株分离的人与胃癌前病变的人与人的胃炎单独。这些结果表明，CagA的缺失防止了该模型中癌症的发展。oipA的失活减弱了P-连环蛋白的核转位，也降低了癌症的发生率。除了确定介导H.这些结果为了解可能调节炎症状态背景下产生的其他恶性肿瘤发展的机制提供了见解。
Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, and strains that possess the cag secretion system, which translocates the bacterial effector CagA into host cells, augment cancer risk. H. pylori strains that express the vacuolating cytotoxin or the outer membrane protein OipA are similarly associated with severe pathologic outcomes. We previously reported that an in vivo adapted H. pylori strain, 7.13, induces gastric adenocarcinoma in rodent models of gastritis. In the current study, we used carcinogenic strain 7.13 as a prototype to define the role of virulence constituents in H. pylori-mediated carcinogenesis. Mongolian gerbils were infected with wild-type strain 7.13 or cagA(-), vacA(-), or oipA(-) mutants for 12 to 52 weeks. All infected gerbils developed gastritis; however, inflammation was significantly attenuated in animals infected with the cagA(-) hut not the vacA(-) or oipA(-) strains. Gastric dysplasia and cancer developed in >50% of gerbils infected with either the wild-type or vacA- strain but in none of the animals infected with the cagA(-) strain. Inactivation of oipA decreased beta-catenin nuclear localization in vitro and reduced the incidence of cancer in gerbils. OipA expression was detected significantly more frequently among H. pylori strains isolated from human subjects with gastric cancer precursor lesions versus persons with gastritis alone. These results indicate that loss of CagA prevents the development of cancer in this model. Inactivation of oipA attenuates P-catenin nuclear translocation and also decreases the incidence of carcinoma. In addition to defining factors that mediate H. pylori-induced cancer, these results provide insight into mechanisms that may regulate the development of other malignancies arising within the context of inflammatory states.