More than half of the world's population is infected with Helicobacter pylori, which causes chronic gastritis and gastric adenocarcinoma. Interventions based on high risk variables are needed. Benefits of antibiotics in reduction of gastric cancer in patients with precancerous lesions are not established. Our studies have directly implicated polyamines, derived from the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric inflammation and carcinogenesis. We have demonstrated that the mechanism leading to H. pylori-induced DNA damage is induction of the enzyme spermine oxidase (SMOX), which is downstream of ODC and generates H2O2 via metabolism of spermine. Polyamines are increased in H. pylori gastritis in mice, and inhibition of ODC reduces H. pylori colonization and gastritis. In the gerbil model of gastric cancer induced by a Colombian high risk strain, polyamine levels correlate with levels of gastritis, DNA damage, and progression to dysplasia/carcinoma, and inhibitors of ODC or SMOX each suppress DNA damage, and reduce rates of dysplasia/carcinoma by more than 50%. SMOX expression increases along the Correa Cascade of histologic lesions from gastritis to precancerous intestinal metaplasia both in North American subjects and in cases from Colombia and Honduras where H. pylori prevalence and gastric cancer rates are amongst the highest in the world. We have also reported that activation of epidermal growth factor receptor (EGFR), via phosphorylation at Y1068 in gastric epithelial cells, is a key molecular event that leads to SMOX induction and DNA damage with H. pylori infection. We implicated a pEGFR?ERBB2 heterodimer that leads to ERBB2 phosphorylation and resulting inhibition of apoptosis in cells with oxidative DNA damage caused by SMOX. We have linked pEGFR and pERBB2, with SMOX, to the Correa Cascade, as epithelial levels of these markers were increased in Colombian subjects that exhibited progression of precancerous lesions during follow-up of a longterm cohort from baseline to year 16, and also increased in high risk Honduran subjects. Our hypothesis is that in human populations at high risk for gastric cancer, H. pylori bacterial determinants and human host genetics drive a distinct molecular signature, involving EGFR signaling and downstream polyamine oxidation by SMOX that mediates H. pylori-induced gastric carcinogenesis. We will interact closely with each of the other Project and the Cores to obtain human samples and H. pylori strains and incorporate analysis of the host and bacterial genetics and the gastric microbiota.
Our Aims are to determine if: 1.) H. pylori factors, including risk region and phylogeographic origin, are crucial in the activation of molecular signatures of carcinogenesis; 2) the molecular signatures of carcinogenesis in high vs. low risk sites in Central America are similar to those in Colombia in the longterm cohort (at years 20 and 24); 3.) strains from high vs. low risk subjects in Central America and from Colombian progressors vs. non-progressors cause more cancer in gerbils. We expect our findings will provide mechanistic insights into gastric carcinogenesis and a molecular basis for gastric cancer prevention.
PROJECT 3 ? Narrative: Stomach cancer is a leading global cause of cancer mortality and a leading infection-associated cancer driven by Helicobacter pylori, a bacterial gastric pathogen that infects more than half of the world's population. Latin America has a high disease burden, as do Hispanic populations in the USA and currently there is no effective strategy to predict or prevent progression of precancerous stomach lesions to cancer. Our studies have implicated molecules called polyamines in gastric cancer development, and in particular an enzyme (spermine oxidase) that acts on one of the polyamines (spermine) to cause damage to DNA; we will now determine both H pylori and human genetic factors that can predict activation of this enzyme and related cellular signaling events in subjects from Colombia and Central America with varying risk for gastric cancer development.
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