| First Author | Yan F | Year | 2009 |
| Journal | Gastroenterology | Volume | 136 |
| Issue | 4 | Pages | 1297-1307, e1-3 |
| PubMed ID | 19250983 | Mgi Jnum | J:148189 |
| Mgi Id | MGI:3843726 | Doi | 10.1053/j.gastro.2008.12.059 |
| Citation | Yan F, et al. (2009) Epidermal growth factor receptor activation protects gastric epithelial cells from Helicobacter pylori-induced apoptosis. Gastroenterology 136(4):1297-1307, e1-3 |
| abstractText | 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. |
