Franco Aime T, Israel Dawn A, Washington Mary K, Krishna Uma, Fox James G, Rogers Arlin B, Neish Andrew S, Collier-Hyams Lauren, Perez-Perez Guillermo I, Hatakeyama Masanori, Whitehead Robert, Gaus Kristin, O'Brien Daniel P, Romero-Gallo Judith, Peek Richard M
Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2279, USA.
Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10646-51. doi: 10.1073/pnas.0504927102. Epub 2005 Jul 18.
Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, yet only a fraction of colonized persons ever develop gastric cancer. The H. pylori cytotoxin-associated gene (cag) pathogenicity island encodes a type IV secretion system that delivers the bacterial effector CagA into host cells after bacterial attachment, and cag+ strains augment gastric cancer risk. A host effector that is aberrantly activated in gastric cancer precursor lesions is beta-catenin, and activation of beta-catenin leads to targeted transcriptional up-regulation of genes implicated in carcinogenesis. We report that in vivo adaptation endowed an H. pylori strain with the ability to rapidly and reproducibly induce gastric dysplasia and adenocarcinoma in a rodent model of gastritis. Compared with its parental noncarcinogenic isolate, the oncogenic H. pylori strain selectively activates beta-catenin in model gastric epithelia, which is dependent on translocation of CagA into host epithelial cells. Beta-catenin nuclear accumulation is increased in gastric epithelium harvested from gerbils infected with the H. pylori carcinogenic strain as well as from persons carrying cag+ vs. cag- strains or uninfected persons. These results indicate that H. pylori-induced dysregulation of beta-catenin-dependent pathways may explain in part the augmentation in the risk of gastric cancer conferred by this pathogen.
幽门螺杆菌引起的持续性胃炎是已知的胃远端腺癌最强风险因素，但只有一小部分感染者会患胃癌。幽门螺杆菌细胞毒素相关基因（cag）致病岛编码一种IV型分泌系统，该系统在细菌附着后将细菌效应蛋白CagA输送到宿主细胞中，cag+菌株会增加患胃癌的风险。在胃癌前病变中异常激活的一种宿主效应蛋白是β-连环蛋白，β-连环蛋白的激活会导致与致癌作用相关基因的靶向转录上调。我们报告称，在体内适应性作用下，一株幽门螺杆菌能够在胃炎啮齿动物模型中快速且可重复地诱发胃发育异常和腺癌。与其亲本非致癌菌株相比，致癌性幽门螺杆菌菌株在模型胃上皮细胞中选择性激活β-连环蛋白，这依赖于CagA转运到宿主上皮细胞中。在感染了幽门螺杆菌致癌菌株的沙鼠以及携带cag+菌株与cag-菌株的人群或未感染者的胃上皮细胞中，β-连环蛋白的核积累均增加。这些结果表明，幽门螺杆菌诱导的β-连环蛋白依赖性途径失调可能部分解释了该病原体导致胃癌风险增加的原因。
