Helicobacter pylori is the strongest known risk factor for gastric cancer;however, not all infected persons develop this malignancy. One H. pylori strain-specific determinant that augments cancer risk is the cag type IV secretion system (TFSS), which translocates the microbial effector CagA into epithelial cells. A host molecule that influences cancer in conjunction with H. pylori is p120-catenin (p120). p120 mediates cell-cell adhesion, but can also aberrantly localize to the nucleus and we have shown that H. pylori induces nuclear translocation of p120 in a cag-dependent manner, which activates the oncogenic transcription factor peroxisome proliferator- activated receptor ? (PPAR?). We have also demonstrated that activation of PPAR? by H. pylori leads to epithelial proliferation via induction of cyclin E1, and that PPAR? expression and epithelial proliferation in rodent and human tissue is selectively induced by cag+ strains. Another p120-mediated response linked to carcinogenesis is epithelial-to-mesenchymal transition (EMT), which is dependent upon a switch in expression of p120 isoforms. Isoform 1 is primarily expressed in fibroblasts while isoform 3 is primarily expressed in epithelial cells and we have shown that H. pylori up-regulates p120 isoform 1 via the cag TFSS and that inhibition of p120 abrogates the induction of molecular markers of EMT by H. pylori. To enhance the translational impact of our work, we will also examine H. pylori isolates harvested from individuals residing in high- or low-risk gastric cancer regions in Colombia. Each region has a high prevalence of H. pylori, providing a unique opportunity to define oncogenic microbial and host mediators. Our hypothesis is that selective activation of p120-dependent pathways by cag+ strains contributes to the augmentation in carcinogenic risk conferred by these strains. We will address this hypothesis via the following Specific Aims: 1. Determine the role of the p120 target PPAR? in regulating host inflammatory and injury responses to H. pylori using in vitro and ex vivo models and human samples. 2. Define the role of PPAR? in regulating host injury responses to H. pylori using in vivo models of PPAR? genetic deficiency and pharmacologic activation. 3. Define H. pylori-induced cellular responses mediated by aberrant activation of p120.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Daschner, Phillip J
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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