Helicobacter pylori is a type I carcinogen and infection with this pathogenic bacterium is considered the leading cause of gastric cancer worldwide. Infection by H. pylori may contribute to malignancy in two distinct ways. The first is by activating a chronic inflammatory response that causes a cascade of molecular and morphologic changes in the inflamed epithelium leading to mucosal atrophy, metaplasia, dysplasia and eventually gastric cancer. The other possibility is that this bacterium may directly modify epithelial cell function and promote carcinogenesis by interfering with genes such as those regulating apoptosis, cell cycle control, tumor suppression and cell-to-cell contacts. These two pathways are mutually non-exclusive as the latter changes are often seen in inflammation. Understanding both mechanisms that underlie how H. pylori causes disease is important, as this could potentially lead to the development of novel therapies. c-Met, also known as the hepatocyte growth factor receptor, is a receptor tyrosine kinase that regulates cell proliferation, differentiation, migration and apoptosis. Dysregulation of c-Met can result in a number of human malignancies including gastric cancer. This proposal examines the hypothesis that c-Met is essential for H. pylori pathogenesis and that through activation of c-Met, other signaling pathways in gastric epithelial cells (GECs) are activated leading to dysregulated cell proliferation. Infection of GECs with H. pylori is known to result in the phosphorylation of c-Met. However, the mechanisms leading to c-Met phosphorylation and the consequences of c-Met activation by H. pylori have not been fully explored. This proposal examines the interaction between H. pylori and c-Met in GECs. Our preliminary data and previously published findings show that: i) H. pylori causes phosphorylation of c-Met;ii) H. pylori infection results in the ectodomain domain shedding of c-Met via activation of A Disintegrin And Metallopeptidase domain-17 (ADAM-17);and that iii) activation of ADAM-17 can mediate shedding of heparin-binding epidermal growth factor (HB-EGF) which in turn culminates in EGFR transactivation.
The specific aims of this study are to: 1) elucidate the upstream signaling pathway that results in c-Met phosphorylation in H. pylori-infected AGS gastric epithelial cells;2) determine the mechanism and role of c-Met ectodomain shedding in response to H. pylori infection;and 3) examine the cross-talk between c-Met and the epidermal growth factor receptor in H. pylori-infected gastric epithelial cells. Results of these studies should lead to a better understanding of the disease mechanisms involved in the development of H. pylori-mediated gastric carcinogenesis.

Public Health Relevance

Helicobacter pylori is a gastric bacterial pathogen that chronically infects over 50% of the world's population and causes diseases ranging from gastritis to gastric cancer. This proposal examines the hypothesis that activation of the hepatocyte growth factor receptor (c-Met) by Helicobacter pylori contributes to the malignant transformation of gastric epithelial cells. Results from these studies should lead to a better understanding of the disease mechanisms involved in the development of H. pylori-mediated gastric carcinogenesis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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Beth Israel Deaconess Medical Center
United States
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