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We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the<jats:italic>H. pylori<\/jats:italic>-induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of<jats:italic>H. pylori<\/jats:italic>-induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of<jats:italic>Egfr<\/jats:italic>(<jats:italic>Efgr<\/jats:italic><jats:sup>\u0394<jats:italic>epi<\/jats:italic><\/jats:sup>mice) were also used.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In C57BL\/6 mice, gefitinib decreased<jats:italic>Cxcl1<\/jats:italic>and<jats:italic>Cxcl2<\/jats:italic>expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by<jats:italic>H. pylori<\/jats:italic>infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected<jats:italic>Egfr<\/jats:italic><jats:sup>\u0394<jats:italic>epi<\/jats:italic><\/jats:sup>versus<jats:italic>Egfr<jats:sup>fl\/fl<\/jats:sup><\/jats:italic>control mice. In<jats:italic>H. pylori<\/jats:italic>-infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked<jats:italic>H. pylo<\/jats:italic>ri-induced activation of mitogen-activated protein kinase 1\/3 (MAPK1\/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1\/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from<jats:italic>Efgr<\/jats:italic><jats:sup>\u0394<jats:italic>epi<\/jats:italic><\/jats:sup>versus<jats:italic>Egfr<jats:sup>fl\/fl<\/jats:sup><\/jats:italic>mice. Epithelial EGFR activation persisted in humans and mice after<jats:italic>H. pylori<\/jats:italic>eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in<jats:italic>H. pylori<\/jats:italic>-infected individuals.<\/jats:p><\/jats:sec>","DOI":"10.1136\/gutjnl-2016-312888","type":"journal-article","created":{"date-parts":[[2017,5,5]],"date-time":"2017-05-05T00:40:22Z","timestamp":1493944822000},"page":"1247-1260","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":70,"title":["Epidermal growth factor receptor inhibition downregulates<i>Helicobacter pylori<\/i>-induced epithelial inflammatory responses, DNA damage and gastric 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