Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells

Sierra, Johanna C.; Hobbs, Stuart S.; Chaturvedi, Rupesh; Yan, Fang; Wilson, Keith T.; Peek, Richard M.; Polk, D. Brent

doi:10.1152/ajpgi.00495.2012

Cited by 34 publications

(29 citation statements)

References 31 publications

(32 reference statements)

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“…12,17 C57BL/6 wild-type (WT) and Egfr wa5 mice possessing an antimorphic EGFR allele that attenuates EGFR phosphorylation, 18 were infected with PMSS1 for 8 weeks.…”

Section: Methodsmentioning

confidence: 99%

Activation of EGFR and ERBB2 by Helicobacter pylori Results in Survival of Gastric Epithelial Cells With DNA Damage

et al. 2014

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BACKGROUND & AIMS The gastric cancer-causing pathogen Helicobacter pylori upregulates spermine oxidase (SMOX) in gastric epithelial cells, causing oxidative stress-induced apoptosis and DNA damage. A subpopulation of SMOXhigh 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 Egfrwa5 mice (which have attenuated EGFR activity), Egfr wild-type mice, or in infected cells incubated with EGFR inhibitors or deficient in EGFR. Phosphoproteomic analysis was performed. Two independent tissue microarrays containing each stage of disease, from gastritis to carcinoma, and gastric biopsies from Colombian and Honduran cohorts were analyzed by immunohistochemistry. RESULTS SMOX expression and DNA damage were decreased, and apoptosis increased in H pylori-infected Egfrwa5 mice. H pylori-infected cells with deletion or inhibition of EGFR had reduced levels of SMOX, DNA damage, and DNA damagehigh apoptosislow cells. Phosphoproteomic analysis revealed increased EGFR and ERBB2 signaling. Immunoblot analysis demonstrated the presence of a phosphorylated (p)EGFR–ERBB2 heterodimer and pERBB2; knockdown of ErbB2 facilitated apoptosis of DNA damagehigh apoptosislow 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 demonstrating 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.

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“…12,17 C57BL/6 wild-type (WT) and Egfr wa5 mice possessing an antimorphic EGFR allele that attenuates EGFR phosphorylation, 18 were infected with PMSS1 for 8 weeks.…”

Section: Methodsmentioning

confidence: 99%

Activation of EGFR and ERBB2 by Helicobacter pylori Results in Survival of Gastric Epithelial Cells With DNA Damage

et al. 2014

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“…A further effect of epithelial contact with the cagPAI type IV secretion system is higher expression of the EGFR and its activation leading to downstream activation of COX2 [197,198]. This is accompanied by a shift towards a proapoptotic homeostasis with increased expression of bax and decreased expression of bcl2 [199,200].…”

Section: Response To H Pylori In the Gastric Mucosamentioning

confidence: 99%

Helicobacter pylori and Gastric Cancer

Bornschein

Malfertheiner

2014

Dig Dis

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Infection with Helicobacter pylori is established as the major risk factor for gastric cancer development. Damage of the mucosal barrier due to H. pylori-induced inflammation enhances the carcinogenic effect of other risk factors such as salt intake or tobacco smoking. The genetic disposition of both the bacterial strain and the host can increase the potential towards gastric cancer formation. Genetic variance of the bacterial proteins CagA and VacA is associated with a higher gastric cancer risk, as are polymorphisms and epigenetic changes in host gene coding for interleukins (IL1β, IL8), transcription factors (CDX2, RUNX3) and DNA repair enzymes. Application of high-throughput assays for genome-wide assessment of either genetic structural variance or gene expression patterns may lead to a better understanding of the pathobiological background of these processes, including the underlying signaling pathways. Understanding of the stepwise alterations that take place in the transition from chronic atrophic gastritis, via metaplastic changes, to invasive neoplasia is vital to define the ‘point of no return' before which eradication of H. pylori has the potential to prevent gastric cancer. Currently, eradication as preventive strategy is only recommended for high-incidence regions in Asia; large population studies with an adequate follow-up are required to demonstrate the effectiveness of such an approach in Western populations.

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“…Consistently, the present study demonstrated that expression of 15-PGDH mRNA and protein was significantly suppressed in gastric cancer samples compared with control samples, and infection with H. pylori resulted in additional downregulation of 15-PGDH mRNA and protein levels. These findings indicated that H. pylori infection may trigger carcinogenesis of stomach cancer by elevating PGE 2 levels through modulating expression of Previous studies have also demonstrated that gastric tumors may be induced by activated macrophages in transgenic mice overexpressing COX-2 and the PGE 2 -converting enzyme microsomal prostaglandin E synthesis (25), and that COX-2 was induced by H. pylori infection (26,27). A significant upregulation of COX-2 was also previously identified in >70% of gastric cancer specimens, and this was reversed when H. pylori was eliminated (28).…”

Section: Discussionmentioning

confidence: 74%

Helicobacterï¿½pylori modulates cyclooxygenase‑2 and 15‑hydroxy prostaglandin dehydrogenase in gastric cancer

et al. 2017

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Abstract. Persistent infection with Helicobacter pylori may contribute to the carcinogenesis of gastric cancer through modulating local prostaglandin E 2 (PGE 2 ) levels. Cyclooxygenase-2 (COX-2) and 15-hydroxy prostaglandin dehydrogenase (15-PGDH) are two key enzymes that regulate PGE 2 synthesis and inactivation, respectively. The present study was designed to investigate the expression of COX-2 and 15-PGDH in gastric cancer specimens (n=66) in comparison to that of control specimens (n=70) and, furthermore, to semi-quantitatively assess the level of COX-2 and 15-PGDH mRNA and protein in tissues with or without H. pylori infection by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. It was revealed that COX-2 was expressed in almost all gastric cancer specimens infected with H. pylori (32 out of 33 specimens), but it was also expressed in 2/3 gastric cancers without H. pylori infection (22 out of 33 specimens). By contrast, COX-2 was expressed in <1/6 control subjects regardless of H. pylori infection. Furthermore, 15-PGDH was expressed in control samples but significantly downregulated in gastric cancer specimens. H. pylori infection resulted in slight inhibition of 15-PGDH in control subjects, but significant inhibition of 15-PGDH mRNA expression and protein synthesis in the gastric cancer specimens. These findings indicated that COX-2 and 15-PGDH, the two enzymes that regulate PGE 2 levels, were significantly altered in gastric cancer, and that H. pylori may contribute to gastric carcinogenesis through modulating COX-2 and 15-PGDH mRNA expression and protein synthesis.

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Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells

Abstract: DB. Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells.

Cited by 34 publications

References 31 publications

Activation of EGFR and ERBB2 by Helicobacter pylori Results in Survival of Gastric Epithelial Cells With DNA Damage

Activation of EGFR and ERBB2 by Helicobacter pylori Results in Survival of Gastric Epithelial Cells With DNA Damage

Helicobacter pylori and Gastric Cancer

Helicobacterï¿½pylori modulates cyclooxygenase‑2 and 15‑hydroxy prostaglandin dehydrogenase in gastric cancer

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