title: Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells.
abstract: Chronic infection of the gastric mucosa by Helicobacter pylori is associated with an increased risk of developing gastric cancer; however, the vast majority of infected individuals never develop this disease. One H. pylori virulence factor that increases gastric cancer risk is the cag pathogenicity island, which encodes a bacterial type IV secretion system. Cyclooxygenase-2 (COX-2) expression is induced by proinflammatory stimuli, leading to increased prostaglandin E₂ (PGE₂) secretion by gastric epithelial cells. COX-2 expression is increased in gastric tissue from H. pylori-infected persons. H. pylori also activates the epidermal growth factor receptor (EGFR) in gastric epithelial cells. We now demonstrate that H. pylori-induced activation of COX-2 in gastric cells is dependent upon EGFR activation, and that a functional cag type IV secretion system and direct bacterial contact are necessary for full induction of COX-2 by gastric epithelial cells. PGE₂ secretion is increased in cells infected with H. pylori, and this induction is dependent on a functional EGFR. Increased apoptosis in response to H. pylori occurs in cells treated with a COX-2 inhibitor, as well as COX-2-/- cells, indicating that COX-2 expression promotes cell survival. In vivo, COX-2 induction by H. pylori is significantly reduced in mice deficient for EGFR activation compared with wild-type mice with a fully functional receptor. Collectively, these findings indicate that aberrant activation of the EGFR-COX-2 axis may lower the threshold for carcinogenesis associated with chronic H. pylori infection.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Sierra
authors.forename: Stuart
authors.initials: S
authors.lastname: Hobbs
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.forename: D Brent
authors.initials: DB
authors.lastname: Polk
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology; D016480:Helicobacter pylori; D051379:Mice; D018345:Mice, Knockout; D013270:Stomach / Q000166:cytology*
chemical_list: C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D015232:Dinoprostone
keywords: EGFR; Helicobacter pylori; cyclooxygenase-2