Epidermal growth factor receptor inhibition downregulates <i>Helicobacter pylori</i>-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis.

Abstract

Gastric cancer is the third leading cause of cancer death worldwide and infection by <i>Helicobacter pylori</i> is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the <i>H. pylori</i>-induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis. We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of <i>H. pylori</i>-induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of <i>Egfr</i> (<i>Efgr</i>^Δ<i>epi</i> mice) were also used. In C57BL/6 mice, gefitinib decreased <i>Cxcl1</i> and <i>Cxcl2</i> expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by <i>H. pylori</i> infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected <i>Egfr</i>^Δ<i>epi</i> versus <i>Egfr^fl/fl</i> control mice. In <i>H. pylori</i>-infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked <i>H. pylo</i>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 <i>Efgr</i>^Δ<i>epi</i> versus <i>Egfr^fl/fl</i> mice. Epithelial EGFR activation persisted in humans and mice after <i>H. pylori</i> eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics. These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in <i>H. pylori</i>-infected individuals.