Pelayo Correa
Faculty Member
Last active: 5/28/2014

Activation of EGFR and ERBB2 by Helicobacter pylori results in survival of gastric epithelial cells with DNA damage.

Chaturvedi R, Asim M, Piazuelo MB, Yan F, Barry DP, Sierra JC, Delgado AG, Hill S, Casero RA, Bravo LE, Dominguez RL, Correa P, Polk DB, Washington MK, Rose KL, Schey KL, Morgan DR, Peek RM, Wilson KT
Gastroenterology. 2014 146 (7): 1739-51.e14

PMID: 24530706 · PMCID: PMC4035375 · DOI:10.1053/j.gastro.2014.02.005

BACKGROUND & AIMS - The gastric cancer-causing pathogen Helicobacter pylori up-regulates spermine oxidase (SMOX) in gastric epithelial cells, causing oxidative stress-induced apoptosis and DNA damage. A subpopulation of SMOX(high) cells are resistant to apoptosis, despite their high levels of DNA damage. Because epidermal growth factor receptor (EGFR) activation can regulate apoptosis, we determined its role in SMOX-mediated effects.

METHODS - SMOX, apoptosis, and DNA damage were measured in gastric epithelial cells from H. pylori-infected Egfr(wa5) mice (which have attenuated EGFR activity), Egfr wild-type mice, or in infected cells incubated with EGFR inhibitors or deficient in EGFR. A phosphoproteomic analysis was performed. Two independent tissue microarrays containing each stage of disease, from gastritis to carcinoma, and gastric biopsy specimens from Colombian and Honduran cohorts were analyzed by immunohistochemistry.

RESULTS - SMOX expression and DNA damage were decreased, and apoptosis increased in H. pylori-infected Egfr(wa5) mice. H. pylori-infected cells with deletion or inhibition of EGFR had reduced levels of SMOX, DNA damage, and DNA damage(high) apoptosis(low) cells. Phosphoproteomic analysis showed increased EGFR and erythroblastic leukemia-associated viral oncogene B (ERBB)2 signaling. Immunoblot analysis showed the presence of a phosphorylated (p)EGFR-ERBB2 heterodimer and pERBB2; knockdown of ErbB2 facilitated apoptosis of DNA damage(high) apoptosis(low) cells. SMOX was increased in all stages of gastric disease, peaking in tissues with intestinal metaplasia, whereas pEGFR, pEGFR-ERBB2, and pERBB2 were increased predominantly in tissues showing gastritis or atrophic gastritis. Principal component analysis separated gastritis tissues from patients with cancer vs those without cancer. pEGFR, pEGFR-ERBB2, pERBB2, and SMOX were increased in gastric samples from patients whose disease progressed to intestinal metaplasia or dysplasia, compared with patients whose disease did not progress.

CONCLUSIONS - In an analysis of gastric tissues from mice and patients, we identified a molecular signature (based on levels of pEGFR, pERBB2, and SMOX) for the initiation of gastric carcinogenesis.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

MeSH Terms (31)

Animals Apoptosis Cell Line Cell Survival Cell Transformation, Neoplastic Coculture Techniques Colombia Disease Progression DNA Damage Enzyme Activation Epithelial Cells ErbB Receptors Gastric Mucosa Gastritis Helicobacter Infections Helicobacter pylori Honduras Humans Metaplasia Mice Mice, Inbred C57BL Mice, Knockout Oxidoreductases Acting on CH-NH Group Donors Phosphorylation Precancerous Conditions Principal Component Analysis Protein Multimerization Receptor, ErbB-2 Signal Transduction Stomach Neoplasms Tennessee

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