Gastric cancer is a major cause of worldwide mortality. Sadly, the disease usually presents at an advanced stage, when resistant to the activation of cell death pathways by chemo-radiation. Insights into the molecular pathogenesis whereby gastric cancer cells acquire resistance to apoptosis may provide more rational targets for therapy in this disease. Gastric cancer is in most cases preceded by and attributable to gastric infection by Helicobacter pylori. Chronic H. pylori infection increases gastric epithelial cell turnover and can lead to apoptosis-resistance associated with low expression of the p27 tumor suppressor protein in chronically-infected gastric epithelial cells. We have recently demonstrated in co-culture experiments that H. pylori decreases the expression of p27 in gastric epithelial cells through accelerated proteasomal degradation of p27 protein and found similar post-translational down-regulation of p27 protein expression in endoscopic biopsies from H. pylori-colonized patients. In addition, we found that mice deficient in p27 frequently develop gastric cancer following H. pylori infection. Based on these findings, we propose to test the hypothesis that H. pylori decreases p27 in gastric epithelial cells by a novel mechanism involving accelerated proteasomal p27 protein degradation resulting in increased susceptibility to gastric cancer, and to characterize the H. pylori-infected p27-deficient mouse as a gastric cancer model for preclinical studies. Specifically, we shall: 1. Determine how H. pylori increases the proteasomal degradation of p27 protein Cell-free and co-culture systems will be utilized to examine the molecular mechanisms of the novel ubiquitin-independent p27 degradative pathway activated by H. pylori that we have identified. 2. Characterize the histological, bacterial and immunological features of our novel model of H. pylori-associated gastric cancer in p27-deficient mice. 3. Utilize the p27-deficient mouse as a preclinical tool to test the effects of H. pylori eradication on gastric cancer susceptibility. These studies focused on the role of p27 in gastric carcinogenesis associated with H. pylori should lead to improved understanding of the mechanisms of gastric carcinogenesis associated with H. pylori infection and provide a novel mouse model of H. pylori-associated gastric carcinogenesis for preclinical testing. Because of the designation of H. pylori by the World Health Organization as a class I (definite) carcinogen in the etiology of the second most frequent cause of worldwide cancer mortality, our findings have important implications for a major global public health problem. Our overall long-term goal is to contribute to the development of new clinical strategies for the prevention, diagnosis and treatment of gastric cancer.
