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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077955-17
Application #
8628746
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
1997-09-30
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
17
Fiscal Year
2014
Total Cost
$336,873
Indirect Cost
$120,929
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Corley, Douglas A; Peek Jr, Richard M (2018) When Should Guidelines Change? A Clarion Call for Evidence Regarding the Benefits and Risks of Screening for Colorectal Cancer at Earlier Ages. Gastroenterology 155:947-949
Sierra, Johanna C; Asim, Mohammad; Verriere, Thomas G et al. (2018) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 67:1247-1260
Noto, Jennifer M; Chopra, Abha; Loh, John T et al. (2018) Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments. Gut 67:1793-1804
Butt, Julia; Blot, William J; Teras, Lauren R et al. (2018) Antibody Responses to Streptococcus Gallolyticus Subspecies Gallolyticus Proteins in a Large Prospective Colorectal Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev 27:1186-1194
Shen, Xi; Liu, Liping; Peek, Richard M et al. (2018) Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes. Mucosal Immunol 11:1316-1328
Mera, Robertino M; Bravo, Luis E; Camargo, M Constanza et al. (2018) Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 67:1239-1246
Xiong, Menghua; Bao, Yan; Xu, Xin et al. (2017) Selective killing of Helicobacter pylori with pH-responsive helix-coil conformation transitionable antimicrobial polypeptides. Proc Natl Acad Sci U S A 114:12675-12680
Zhu, Shoumin; Soutto, Mohammed; Chen, Zheng et al. (2017) Helicobacter pylori-induced cell death is counteracted by NF-?B-mediated transcription of DARPP-32. Gut 66:761-762
Suarez, Giovanni; Romero-Gallo, Judith; Sierra, Johanna C et al. (2017) Genetic Manipulation of Helicobacter pylori Virulence Function by Host Carcinogenic Phenotypes. Cancer Res 77:2401-2412
Noto, Jennifer M; Peek Jr, Richard M (2017) Helicobacter pylori Makes a Molecular Incision to Gain Epithelial Entry. Cell Host Microbe 22:434-436

Showing the most recent 10 out of 123 publications