title: Epidermal growth factor receptor activation protects gastric epithelial cells from Helicobacter pylori-induced apoptosis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.forename: Hanwei
authors.initials: H
authors.lastname: Cao
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Uma
authors.initials: U
authors.lastname: Krishna
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Hobbs
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dempsey
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Cover
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.forename: D Brent
authors.initials: DB
authors.lastname: Polk
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D016480:Helicobacter pylori; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013270:Stomach / Q000382:microbiology* / Q000473:pathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse