Mechanisms of Helicobacter pylori virulence and beta-catenin activation in gastric carcinogenesis

Gastric cancer is the 2nd leading cause of cancer related death world-wide, and Helicobacter pylori is the strongest identifiable risk factor for this disease. We have utilized an in vivo-adapted H. pylori isolate, 7.13, that rapidly and reproducibly induces gastric cancer in Mongolian gerbils to define bacterial and host factors which regulate gastric carcinogenesis.;The goal of this dissertation project is to define mechanisms that regulate the carcinogenic potential of strain 7.13. We found that the carcinogenic strain selectively upregulates the host effector beta-catenin in gastric epithelial cells. This response was dependent on the bacterial effector CagA. H. pylori does not induce beta-catenin through canonical Wnt signaling, inhibition of proteasome-mediated degradation, or through transcriptional regulation, perhaps representing a novel mechanism of beta-catenin regulation.;Utilizing a proteomic approach, we also characterized the proteomes of carcinogenic strain 7.13 and its parental derivative B128. Twenty-eight proteins were found to be differentially regulated between the two strains. In functional assays carcinogenic strain 7.13 was found to be more motile in soft agar, and possessed flagella that were significantly longer in relation to the length of bacterium compared to strain B128. The observed differences in protein expression and phenotype may represent mechanisms by which strain 7.13 exerts a more pathogenic phenotype.;Finally, we used carcinogenic strain 7.13 to infect Mongolian gerbils for 12-52 weeks to define the role of bacterial factors in inflammation and carcinogenesis. We found that the bacterial factor CagA is essential for cancer development in this model. Cancer developed in gerbils infected with the wild-type H. pylori strain as early as 12 weeks post-infection; however, no cancer developed in gerbils infected with the cagA- mutant strain as long as 53 weeks post-infection.;Collectively, these studies have defined H. pylori bacterial factors that are essential for transformation, perhaps through deregulation of host pathways such as beta-catenin signaling. These findings provide a framework for future studies investigating the development of cancer within the context of microbial induced chronic inflammation.