Helicobacter pylori infects half the world and is the principal cause of gastric cancer, the second leading cause of cancer death worldwide. However, universal eradication is not feasible and there is a strong need to identify persons at high risk for cancer development and develop new strategies for intervention. We have directly implicated phosphorylation of the epidermal growth factor receptor (pEGFR) and induction of spermine oxidase (SMO) in the aberrant signaling response to H. pylori in gastric epithelial cells. Our published and preliminary data show that oxidation of the polyamine spermine by SMO results in generation of H2 02 that is the cause of DNA damage in infected gastric epithelial cells, and that pEGFR is required for SMO expression and mediates the generation of a subpopulation of cells with SMO-driven DNA damage that are resistant to apoptosis. These events occur in conditionally immortalized gastric epithelial cells and in in vivo models of gastric carcinogenesis (INS-GAS mice and Mongolian gerbils), and human tissues exhibit a strong correlation of SMO and DNA damage. Inhibition of polyamine synthesis or SMO reduces gastric dysplasia and carcinoma in gerbils. Our phosphoproteomics and human tissue microarray studies have implicated EGFR and ErbB2 signaling in addition to SMO in the initiation of gastric carcinogenesis. Additionally, depletion of polyamines in vitro and in vivo reduces oxidative DNA damage and carcinoma despite substantially increasing pEGFR. Our hypothesis is that polyamines determine the effects of EGFR phosphorylation on H. pylori-induced inflammation, DNA damage, and gastric carcinogenesis.
Our Specific Aims are to determine the following in H. pylori-induced gastric carcinogenesis: 1) the role of EGFR transactivation and apoptosis-resistant cells;2) if polyamines are required for the deleterious effects of pEGFR;and 3) the positive and negative regulators of EGFR signaling that are involved. These studies will incorporate unique in vitro and ex vivo models such as gastric organoids, and proven models of gastric dysplasia and carcinoma in mice and gerbils that are employed across this PPG to pursue these aims. We will benefit from continued close collaborations with Projects 1 and 3 that will include exchange of H. pylori mutant strains and output strains from our different animals systems, sharing of samples and expertise related to signaling, and our analysis of SMO-induced oxidative stress and DNA damage. This project will leverage the exceptional quality of Histopathology Core A for Aims 1-3 and Proteomics Core 8 for Aim 3, and will benefit from the uniquely strong environment at Vanderbilt for studies of H. pylori and gastric cancer.

Public Health Relevance

Helicobacter pylori is a type of bacteria that infects the stomach of half of the world's human population, and can lead to the development of gastric cancer, the second leading cause of cancer death worldwide. This project will utilize cell and animal model systems to assess novel molecular pathways altered by H. pylori that lead to cells with damaged DNA that are abnormally resistant to cell death. Our studies seek to define new strategies for prevention of H. pylori-induced gastric cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA116087-06
Application #
8632348
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (O1))
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2014-03-12
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$280,150
Indirect Cost
$81,541
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Chaturvedi, R; de Sablet, T; Asim, M et al. (2015) Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase. Oncogene 34:3429-40
Krakowiak, M S; Noto, J M; Piazuelo, M B et al. (2015) Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization. Oncogene 34:1865-71
Wei, Jinxiong; Noto, Jennifer M; Zaika, Elena et al. (2015) Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner. Gut 64:1040-8
Wroblewski, Lydia E; Piazuelo, M Blanca; Chaturvedi, Rupesh et al. (2015) Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells. Gut 64:720-30
Gobert, Alain P; Verriere, Thomas; Asim, Mohammad et al. (2014) Heme oxygenase-1 dysregulates macrophage polarization and the immune response to Helicobacter pylori. J Immunol 193:3013-22
Wang, Dingzhi; Fu, Lingchen; Ning, Wei et al. (2014) Peroxisome proliferator-activated receptor ? promotes colonic inflammation and tumor growth. Proc Natl Acad Sci U S A 111:7084-9
Chaturvedi, Rupesh; Asim, Mohammad; Barry, Daniel P et al. (2014) Spermine oxidase is a regulator of macrophage host response to Helicobacter pylori: enhancement of antimicrobial nitric oxide generation by depletion of spermine. Amino Acids 46:531-42
Kodaman, Nuri; Pazos, Alvaro; Schneider, Barbara G et al. (2014) Human and Helicobacter pylori coevolution shapes the risk of gastric disease. Proc Natl Acad Sci U S A 111:1455-60
Abreu, Maria T; Peek Jr, Richard M (2014) Gastrointestinal malignancy and the microbiome. Gastroenterology 146:1534-1546.e3
Van Kaer, Luc; Algood, Holly M Scott; Singh, Kshipra et al. (2014) CD8??? innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity. Immunity 41:451-64

Showing the most recent 10 out of 86 publications