Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. H. pylori is the strongest known risk factor for this malignancy, yet only a fraction of infected persons ever develop cancer. One H. pylori determinant that augments cancer risk is the cag pathogenicity island, and several cag genes encode components of a type IV bacterial secretion system which functions to export proteins (e.g., CagA) into host epithelial cells. A host effector that may influence carcinogenesis is ?-catenin, a downstream component of the Wnt pathway. When Wnt signaling is inactive, ??catenin is constitutively phosphorylated and degraded; binding of Wnt to its receptor inhibits ?-catenin phosphorylation, leading to its nuclear accumulation and the transcriptional activation of genes that influence carcinogenesis. Nuclear accumulation of ?-catenin is increased in gastric adenoma and dysplasia specimens, histologic stages that precede gastric adenocarcinoma. Our preliminary studies now demonstrate that a rodent-adapted H. pylori cag+ strain (7.13) rapidly induces gastric cancer in hypergastrinemic (INS-GAS) mice by 24 weeks and in Mongolian gerbils by 4 weeks. H. pylori strain 7.13 also induces nuclear translocation of ?-catenin and activates a ?-catenin-responsive reporter in vitro, indicating that ?-catenin is functionally responsive to this prototype strain. ?-catenin activation by H. pylori is dependent upon translocation of CagA into epithelial cells, and nuclear accumulation of ?-catenin is increased in gastric epithelium harvested from cag+-infected persons, compared to subjects carrying cag- strains or uninfected persons. Our hypothesis is that H. pylori cag+ strains selectively activate host signaling pathways, such as those mediated by ?-catenin, thereby regulating cellular responses that contribute to the augmentation in carcinogenic risk associated with these strains. Thus, our specific aims are: 1. To define the effects of H. pylori constituents on activation of ?-catenin in vitro and in vivo. 2. To define the host signaling pathways that regulate H. pylori-induced ?-catenin activation. 3. To define differences in epithelial molecular responses to carcinogenic H. pylori versus mutant strains using a transgenic murine model of gastric cancer. ? ? ?
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