H. py/or/-induced gastric tumorigenesis is associated with dysregulation of gastric epithelial apoptosis and aroliferation;yet, the mechanisms that govern these cellular responses are unclear. H. pylori induces gastric epithelial cell activation of epidermal growth factor receptor (EGFR) and a downstream target, ERK1/2. These signaling pathways regulate cellular proliferation and survival programs implicated in tumorigenesis in other systems and our data now indicate that H. pylori activation of EGFR attenuates apoptosis. Our preliminary findings also show that a disintegrin and metalloproteinase- (ADAM-) 17 expression is required for EGFR transactivation by H. pylori and that activation of EGFR mediates H. py/ori-induced oxidative stress through up-regulation of spermine oxidase (SMO). Therefore, we hypothesize that transactivation of EGFR is a key molecular regulatory step in the pathogenesis of H. py/ori-mediated tumorigenesis, initiating anti-apoptotic responses that heighten the retention of cells mutagenized by this pathogen.
Three Specific Aims are designed to achieve this goal: 1. Determine the mechanism of activation of EGFR and the molecular interactions regulated by H. pylori. We will focus on the requirement of ADAM- 17 for EGFR activation using ADAM-17 knockout and add-back cell lines and specific inhibitors. EGFR interacting proteins will be precipitated with Flag-EGFR and identified by MALDI-TOF analysis. 2. Define the contribution of EGFR transactivation and identify downstream targets in H. py/or/-mediated gastric epithelial cell DMA damage. We will assess the role of SMO as a downstream target of EGFR transactivation, determine oxidative injury and DMA damage, and use 2D-DIGE to identify downstream targets of H. py/or/'-mediated EGFR transactivation. 3. Determine the effects of EGFR transactivation on H. py/or/-mediated gastric epithelial cell DMA damage, apoptosis, proliferation, and tumorigenesis in vivo. Proliferation, apoptosis, stress responses, and cancer precursor lesions will be analyzed in H. pyloriinfected wild-type and EGFR-defective mice. The significance of this research is to determine the molecular mechanism(s) of H. py/or/-mediated gastric epithelial cell survival within the context of mutagenesis pathways leading to gastric tumorigenesis, which is important for identifying novel therapeutic targets for H. py/ori-mediated diseases. Furthermore, these mechanisms may be implicated in a number of inflammationassociated intestinal disorders resulting from altered programs of cellular proliferation and apoptosis.
|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|
|Singh, Kshipra; Coburn, Lori A; Asim, Mohammad et al. (2018) Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses. Cancer Res 78:4303-4315|
|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|
|Gobert, Alain P; Al-Greene, Nicole T; Singh, Kshipra et al. (2018) Distinct Immunomodulatory Effects of Spermine Oxidase in Colitis Induced by Epithelial Injury or Infection. Front Immunol 9:1242|
|Raghunathan, Krishnan; Foegeding, Nora J; Campbell, Anne M et al. (2018) Determinants of Raft Partitioning of the Helicobacter pylori Pore-Forming Toxin VacA. Infect Immun 86:|
|Scoville, Elizabeth A; Allaman, Margaret M; Brown, Caroline T et al. (2018) Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Metabolomics 14:|
|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|
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