Helicobacter pylori is the strongest known risk factor for gastric adenocarcinoma, yet only a fraction of infected persons ever develop cancer. One H. pylori determinant that augments cancer risk is the cag pathogenicity island, which translocates bacterial proteins into host cells following adherence. Since contact between H. pylori and gastric epithelial cells is critical for induction of injury, the long-term objective of R01 grant CA 77955 is to define mechanisms through which H. pylori induce epithelial responses with carcinogenic potential. A host molecule that may influence carcinogenesis in conjunction with H. pylori is matrix metalloproteinase-7 (MMP-7). MMP-7 attenuates apoptosis and we have demonstrated that MMP-7 is expressed exclusively in human mucosa colonized by H. pylori cag+ strains and that these strains selectively induce MMP-7 through cag-mediated activation of ERK1/2. Our studies now show that up-regulation of MMP-7 by H. pylori also requires p120-catenin (p120). p120 functions as a transcription factor by forming complexes with Kaiso, a transcriptional repressor implicated in tumorigenesis. Over-expression of p120 relieves Kaiso-mediated transcriptional repression of MMP-7, and our data show that H. pylori-induced up-regulation of MMP-7 is mediated by p120 and Kaiso in vitro and in an ex vivo gastric gland culture model system. Rodent models provide valuable insights into gastric carcinogenesis, and our studies now demonstrate that a rodent-adapted derivative (7.13) of a human H. pylori cag+ strain induces gastric cancer in Mongolian gerbils by 4 weeks and in hypergastrinemic (INS-GAS) mice by 24 weeks. Using this strain as a prototype, we show that strain 7.13 selectively activates epidermal growth factor receptor (EGFR) and ERK1/2, a downstream mediator of EGFR, in vitro. Activation of EGFR attenuates apoptosis in response to strain 7.13 and is required for up-regulation of MMP-7. Since EGFR transactivation can directly phosphorylate p120, our hypothesis is that selective activation of p120-dependent pathways by H. pylori cag+ strains contributes to the augmentation in carcinogenic risk conferred by these strains by attenuating epithelial apoptosis.
Our specific aims are: 1. To define the effects of wild-type and isogenic mutant H. pylori strains on p120-dependent cellular responses related to carcinogenesis in vitro. 2. To define the host signaling pathways that regulate H. pylori-induced p120 activation. 3. To define the effects of p120 and EGFR on H. pylori-induced injury in vivo.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077955-15
Application #
8239912
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
1997-09-30
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
15
Fiscal Year
2012
Total Cost
$341,152
Indirect Cost
$118,529
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
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
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
Varga, Matthew Gordon; Peek, Richard M (2017) DNA Transfer and Toll-like Receptor Modulation by Helicobacter pylori. Curr Top Microbiol Immunol 400:169-193
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

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