Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. H. pylori is the strongest known risk factor for this malignancy, yet only a fraction of infected persons ever develop cancer. One H. pylori determinant that augments cancer risk is the cag pathogenicity island, and several cag genes encode components of a type IV bacterial secretion system which functions to export proteins (e.g., CagA) nto host epithelial cells. A host effector that may influence carcinogenesis is li-catenin, a downstream component of the Wnt pathway. When Wnt signaling is inactive, (l-catenin is constitutively phosphorylated and degraded;binding of Wnt to its receptor inhibits G-catenin phosphorylation, leading to its nuclear accumulation and the transcriptional activation of genes that influence carcinogenesis. Nuclear accumulation of fi-catenin is increased in gastric adenoma and dysplasia specimens, histologic stages that precede gastric adenocarcinoma. Our preliminary studies now demonstrate that a rodent-adapted H. pylori ?ag+ strain (7.13) rapidly induces gastric cancer in hypergastrinemic (INS-GAS) mice by 24 weeks and in Vlongolian gerbils by 4 weeks and that strain 7.13 induces nuclear translocation of G-catenin and activates a B-catenin-responsive reporter in vitro, indicating that li-catenin is functionally responsive to this prototype strain. IS-catenin activation by H. pylori is dependent upon translocation of CagA into epithelial cells, and nuclear accumulation of U-catenin is increased in gastric epithelium harvested from cag+-infected persons, compared to subjects carrying cag strains or uninfected persons. Our hypothesis is that H. pylori cag* strains selectively activate host signaling pathways, such as those mediated by R-catenin, thereby regulating cellular responses that contribute to the augmentation in carcinogenic risk associated with these strains. Thus, our specific aims are: 1. To define the effects of H. pylori constituents on activation of S-catenin in vitro and in vivo. 2. To determine the eukaryotic signaling pathways that regulate H. py/or/-induced fi-catenin activation. 3. To define differences in epithelial molecular responses to carcinogenic H. pylori versus mutant strains using a transgenic murine model of gastric cancer.
These studies will define bacterial and host factors that influence gastric cancer. Such findings may help to identify H. pylori infected persons at high risk for gastric cancer, who thereby warrant therapy.
|Hardbower, Dana M; Singh, Kshipra; Asim, Mohammad et al. (2016) EGFR regulates macrophage activation and function in bacterial infection. J Clin Invest 126:3296-312|
|Riquelme, Ismael; Tapia, Oscar; Leal, Pamela et al. (2016) miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway. Cell Oncol (Dordr) 39:23-33|
|Gogoi, Mayuri; Datey, Akshay; Wilson, Keith T et al. (2016) Dual role of arginine metabolism in establishing pathogenesis. Curr Opin Microbiol 29:43-8|
|Gobert, Alain P; Wilson, Keith T (2016) The Immune Battle against Helicobacter pylori Infection: NO Offense. Trends Microbiol 24:366-76|
|Beceiro, S; Radin, J N; Chatuvedi, R et al. (2016) TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection. Mucosal Immunol :|
|Zhao, Gang; Liu, Liping; Peek Jr, Richard M et al. (2016) Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth. J Biol Chem 291:20462-72|
|Peek Jr, Richard M (2016) New Biology to New Treatment of Helicobacter pylori-Induced Gastric Cancer. Dig Dis 34:510-6|
|Chen, Jinjing; Wang, Zhen; Hu, Xiangming et al. (2016) BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation. J Immunol 196:4132-42|
|Amieva, Manuel; Peek Jr, Richard M (2016) Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology 150:64-78|
|Varga, Matthew G; Piazuelo, M Blanca; Romero-Gallo, Judith et al. (2016) TLR9 activation suppresses inflammation in response to Helicobacter pylori infection. Am J Physiol Gastrointest Liver Physiol 311:G852-G858|
Showing the most recent 10 out of 166 publications