Helicobacter pylori induces up-regulation of the epidermal growth factor receptor in AGS gastric epithelial cells.
BACKGROUND
Helicobacter pylori infection increases the risk of gastric carcinogenesis. The aim of the present study was to determine whether H. pylori could up-regulate the expression of the epidermal growth factor receptor (EGFR), a critical gene in the carcinogenic process.


METHODS
AGS gastric epithelial cells were infected with cag(+) toxigenic or cag(-) nontoxigenic strains of H. pylori or isogenic mutants. EGFR protein expression was determined by Western blotting and immunofluorescence. EGFR mRNA levels were evaluated using real-time polymerase chain reaction. The signaling pathways leading to EGFR up-regulation were examined using the ERK1/2 inhibitor PD98059, the Src inhibitor pp2, the nuclear factor- kappa B inhibitor caffeic acid phenethyl ester, EGFR neutralizing antibodies, and the EGFR kinase inhibitor AG1478.


RESULTS
Infection of AGS cells by H. pylori significantly increased EGFR mRNA and protein levels. We found that this effect was limited to cag(+) H. pylori strains and that mutants with a defective type IV secretion system were unable to cause EGFR up-regulation. Increased EGFR expression was found to be dependent on EGFR receptor transactivation, ERK1/2 phosphorylation, and Src activation.


CONCLUSIONS
Infection of gastric epithelial cells by H. pylori triggers an autocrine loop whereby EGFR transactivation leads to the up-regulation of EGFR expression. This, in turn, may contribute to unrestrained epithelial cell proliferation and carcinogenesis.
Keates
Sarah
S
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. skeates@bidmc.harvard.edu
Keates
Andrew C
AC
Katchar
Kianoosh
K
Peek
Richard M
RM
Kelly
Ciaran P
CP
D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000382:microbiology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism; D020869:Gene Expression Profiling; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000166:cytology / Q000382:microbiology*; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D012333:RNA, Messenger; C080866:cagA protein, Helicobacter pylori; D066246:ErbB Receptors; D019061:src-Family Kinases; D048052:Mitogen-Activated Protein Kinase 3