Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. The strongest risk factor for the development of gastric cancer is chronic inflammation induced by the bacterial pathogen Helicobacter pylori. Adherence of H. pylori to gastric epithelium is a critical step for establishing persistence and permitting survival of this bacterium within the gastric mucosa. Sequence analysis of H. pylori genomes has revealed a large number of predicted outer membrane proteins, many of which have been identified as adhesins, important in H. pylori pathogenesis. This large repertoire of adhesins likely influences virulence of H. pylori by promoting pathologic microbial-host cell interactions. Decay-accelerating factor (DAF) or CD55 is a protein that protects cells from complement-mediated lysis and is also recognized as a receptor by a number of microbial pathogens. DAF was recently identified by our laboratory as a novel receptor that mediates adherence of H. pylori to host epithelial cells. DAF is significantly upregulated in the presence of H. pylori and contributes to H. pylori-mediated gastric inflammation in murine models of gastric cancer. H. pylori-mediated gastric inflammation is dependent on the presence of DAF, as DAF-deficient mice exhibited no inflammation compared with wild-type mice. Recent in vitro work in our lab has revealed a limited number of H. pylori candidate proteins that interact with recombinant DAF. We hypothesize that DAF-mediated adherence of H. pylori to the gastric epithelium is dependent on these microbial proteins and that these interactions activate host cell signaling pathways that are involved in the progression of gastritis to gastric adenocarcinoma. Therefore, the Specific Aims of this application are (1) to define H. pylori constituents required for DAF-mediated adherence to gastric epithelial cells;(2) to identify DAF-mediated H. pylori-induced host cell alterations and tight junction disruption;and finally (3) to determine the role of DAF and DAF-binding adhesins in H. pylori- mediated inflammation, gastric injury, and development of gastric cancer in vivo. The overall aim of this grant application is to further elucidate the complex interactions between H. pylori and host cells that result in progression toward gastric cancer, with the ultimate goal of identifying novel bacterial and/or host targets for prevention and/or therapy of H. pylori-mediated carcinogenesis.

Public Health Relevance

The strongest known risk factor for gastric cancer is colonization by the bacterial pathogen Helicobacter pylori. Preliminary studies have demonstrated the importance of a host protein Decay-accelerating factor (DAF) in H. pylori colonization and chronic inflammation. Therefore, these studies will define H. pylori factors critical for DAF-mediated colonization and delineate the importance of this interaction in H. pylori-induced carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA153539-03
Application #
8315743
Study Section
Special Emphasis Panel (ZRG1-F13-C (20))
Program Officer
Jakowlew, Sonia B
Project Start
2010-09-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$55,670
Indirect Cost
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
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
Noto, Jennifer M; Gaddy, Jennifer A; Lee, Josephine Y et al. (2013) Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans. J Clin Invest 123:479-92
Noto, Jennifer M; Khizanishvili, Tinatin; Chaturvedi, Rupesh et al. (2013) Helicobacter pylori promotes the expression of Kr├╝ppel-like factor 5, a mediator of carcinogenesis, in vitro and in vivo. PLoS One 8:e54344