Keith Wilson
Faculty Member
Last active: 11/2/2019

Epidermal growth factor receptor inhibition downregulates -induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis.

Sierra JC, Asim M, Verriere TG, Piazuelo MB, Suarez G, Romero-Gallo J, Delgado AG, Wroblewski LE, Barry DP, Peek RM, Gobert AP, Wilson KT
Gut. 2018 67 (7): 1247-1260

PMID: 28473630 · PMCID: PMC5671361 · DOI:10.1136/gutjnl-2016-312888

OBJECTIVE - Gastric cancer is the third leading cause of cancer death worldwide and infection by is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the -induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis.

DESIGN - We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of -induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of ( mice) were also used.

RESULTS - In C57BL/6 mice, gefitinib decreased and expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected versus control mice. In -infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked 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 versus mice. Epithelial EGFR activation persisted in humans and mice after eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics.

CONCLUSIONS - These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in -infected individuals.

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MeSH Terms (14)

Animals Antineoplastic Agents Cell Culture Techniques Epithelial Cells ErbB Receptors Gastritis Gefitinib Gerbillinae Helicobacter Infections Helicobacter pylori Mice Mice, Inbred C57BL Quinazolines Stomach Neoplasms

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