Gastric adenocarcinoma is the third leading cause of cancer-related death in the world. Helicobacter pylori is the strongest identified risk factor for this malignancy, yet only a subset of colonized persons ever develop neoplasia. One H. pylori determinant associated with increased gastric cancer risk is the cag pathogenicity island, and several cag genes encode components of a type IV secretion system (T4SS) which exports a bacterial oncoprotein, CagA, into host cells. Our group has demonstrated that H. pylori cag+ strains selectively activate ?-catenin and a stem cell population marked by Lrig1, as well as the EGF receptor and ornithine decarboxylase (ODC), host effectors that influence carcinogenesis. We have made the discovery that formation of a novel amino acid, hypusine, from the polyamine spermidine by deoxyhypusine synthase (DHPS) is upregulated by H. pylori and leads to targeted translation of mRNAs encoding for pro-inflammatory proteins, specifically in macrophages. We have also demonstrated that environmental factors associated with gastric cancer, such as iron deficiency or a high salt diet, augment the ability of H. pylori to induce gastric cancer via the cag T4SS. Therefore, the overarching objective of this application is delineation of the molecular signaling events initiated by H. pylori-host cell contact that regulate phenotypes related to gastric carcinogenesis. This PPG will integrate studies of host-pathogen interactions initiated by biomedical researchers who have made a strong and clear commitment to research within the fields of cancer biology, carcinogenesis, gastroenterology, and microbiology, and will generate results that would not be attainable through independent investigation. The component projects are driven by discrete hypotheses, yet are cohesive in that each focuses on H. pylori-host interactions that induce cellular responses with carcinogenic potential: Project 1. Effect of iron deprivation on H. pylori-induced gastric carcinogenesis (PI-Richard Peek). Project 2. EGFR, ODC and the hypusome in H. pylori-induced gastric cancer (PI-Keith T. Wilson). Project 3. Regulation of H. pylori virulence by dietary factors that impact gastric cancer (PI-Timothy Cover). The efforts of each Project will be further unified by dynamic interactions with Specific Core facilities, which include the Gastric Histopathology Core (Core A), the Proteomics and Metabolomics Core (Core B), and an Administrative Core (Core C). By maintaining a grounded focus on fundamental interactions that occur at the H. pylori:host interface, results from this proposal will not only improve our understanding of gastric cancer, but will also identify potential therapeutic targets for prevention and more effective treatment of this disease.

Public Health Relevance

Overall Narrative This research will define host, bacterial, and dietary factors important in gastric cancer. This information can then be used to identify and treat infected persons at increased risk for this disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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Daschner, Phillip J
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Vanderbilt University Medical Center
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Singh, Kshipra; Coburn, Lori A; Asim, Mohammad et al. (2018) Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses. Cancer Res 78:4303-4315
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