Gastric adenocarcinoma is strongly associated with the presence of H. pylori. Microbial factors of H. pylori and host responses induced by the interactions of H. pylori with gastric epithelial cells play important roles in the development of disease. PI3K and β-catenin/p120 are multifunctional host proteins that coordinate carcinogenic epithelial responses when aberrantly activated, such as in malignant gastric lesions. We demonstrate that H. pylori infection results in upregulation of PI3K-AKT signaling, through stimulation of EGFR. Activation of this pathway reduces rates of epithelial cell death induced by H. pylori and promotes resistance to apoptosis. We also demonstrate that H. pylori infection induces additional host signaling pathways to potentiate a proliferative response in gastric epithelial cells. Specifically, PPARδ, a target of β-catenin transcriptional activation, contributes to increased rates of gastric epithelial cell proliferation in response to H. pylori infection. Based on these findings we hypothesize that an anti-apoptotic response in the presence of increased proliferation increases the risk of retaining mutagenized gastric epithelial cells in the presence of H. pylori induced gastritis. Taken together, these studies have identified effectors that directly mediate host responses related to carcinogenesis. Molecular delineation of such pathways activated by host-microbial interactions will improve our understanding of H. pylori-induced carcinogenesis, allowing for targeted therapies to high-risk individuals, as well as provide insight into other malignancies that arise within the context of pathogen-induced inflammation.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11122009-131410 |
| Date | 13 November 2009 |
| Creators | Nagy, Toni Ann |
| Contributors | Timothy L. Cover, Christopher S. Williams, Wael El-Rifai, Richard M. Peek, Jr. |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11122009-131410/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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