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Epidermal growth factor receptor activation protects gastric epithelial cells from Helicobacter pylori-induced apoptosis.

Yan F, Cao H, Chaturvedi R, Krishna U, Hobbs SS, Dempsey PJ, Peek RM, Cover TL, Washington MK, Wilson KT, Polk DB
Gastroenterology. 2009 136 (4): 1297-1307, e1-3

PMID: 19250983 · PMCID: PMC2878739 · DOI:10.1053/j.gastro.2008.12.059

BACKGROUND & AIMS - Helicobacter pylori infection disrupts the balance between gastric epithelial cell proliferation and apoptosis, which is likely to lower the threshold for the development of gastric adenocarcinoma. H pylori infection is associated with epidermal growth factor (EGF) receptor (EGFR) activation through metalloproteinase-dependent release of EGFR ligands in gastric epithelial cells. Because EGFR signaling regulates cell survival, we investigated whether activation of EGFR following H pylori infection promotes gastric epithelial survival.

METHODS - Mouse conditionally immortalized stomach epithelial cells (ImSt) and a human gastric epithelial cell line, AGS cells, as well as wild-type and kinase-defective EGFR (EGFRwa2) mice, were infected with the H pylori cag+ strain 7.13. Apoptosis, caspase activity, EGFR activation (phosphorylation), and EGFR downstream targets were analyzed.

RESULTS - Inhibiting EGFR kinase activity or decreasing EGFR expression significantly increased H pylori-induced apoptosis in ImSt. Blocking H pylori-induced EGFR activation with a heparin-binding (HB)-EGF neutralizing antibody or abrogating a disintegrin and matrix metalloproteinase-17 (ADAM-17) expression increased apoptosis of H pylori-infected AGS and ImSt, respectively. Conversely, pretreatment of ImSt with HB-EGF completely blocked H pylori-induced apoptosis. H pylori infection stimulated gastric epithelial cell apoptosis in EGFRwa2 but not in wild-type mice. Furthermore, H pylori-induced EGFR phosphorylation stimulated phosphotidylinositol-3'-kinase-dependent activation of the antiapoptotic factor Akt, increased expression of the antiapoptotic factor Bcl-2, and decreased expression of the proapoptotic factor Bax.

CONCLUSIONS - EGFR activation by H pylori infection has an antiapoptotic effect in gastric epithelial cells that appears to involve Akt signaling and Bcl family members. These findings provide important insights into the mechanisms of H pylori-associated tumorigenesis.

MeSH Terms (21)

ADAM17 Protein ADAM Proteins Animals Apoptosis bcl-2-Associated X Protein Caspase 3 Cell Line Cell Proliferation Disease Models, Animal Epithelial Cells ErbB Receptors Gastric Mucosa Helicobacter Infections Helicobacter pylori Humans Mice Mice, Transgenic Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2 Signal Transduction Stomach

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