Transactivation of the epidermal growth factor receptor by cag+ Helicobacter pylori induces upregulation of the early growth response gene Egr-1 in gastric epithelial cells.
OBJECTIVE
Helicobacter pylori, in particular cytotoxin associated gene (cag)+ strains, have been shown to enhance gastric epithelial cell proliferation in vivo, an effect that likely contributes to gastric carcinogenesis. Early growth response gene 1 (Egr-1) is a crucial regulator of cell growth, differentiation, and survival, which is known to play a role in carcinogenesis and cancer progression. The aims of this study were to: (1) examine whether H pylori could upregulate Egr-1 in gastric epithelial cell lines; (2) determine whether there was a differential response to infection with different strains; (3) examine the role of the cag pathogenicity island in this process; and (4) elucidate the molecular mechanisms leading to Egr-1 upregulation.


RESULTS
We found that infection of AGS cells with cag+H pylori resulted in a rapid (1-2 hours) but transient increase in Egr-1 mRNA and protein levels whereas coculture with cag- isolates did not elicit this response. Furthermore, two independent cagE- isogenic mutants of H pylori also demonstrated impaired ability to upregulate Egr-1. Upregulation of Egr-1 protein was inhibited by the extracellular regulated kinase (ERK)1/2 inhibitor PD98059 and overexpression of dominant negative MEK1 downregulated Egr-1 luciferase reporter gene activity. Treatment of AGS cells with the epidermal growth factor receptor (EGFR) kinase inhibitors PD153035 and AG1478 resulted in a reduction in H pylori mediated Egr-1 upregulation, demonstrating that EGFR transactivation plays a role in this early cellular process.


CONCLUSIONS
Our findings show that cag+H pylori cause rapid induction of Egr-1 in gastric epithelial cells which may contribute to H pylori mediated pathogenesis.
Keates
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S
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. skeates@bidmc.harvard.edu
Keates
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Nath
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Peek
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Kelly
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CP
D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D002460:Cell Line; D003603:Cytotoxins / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D016480:Helicobacter pylori / Q000235:genetics*; D006801:Humans; D049453:Luciferases, Bacterial / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D012329:RNA, Bacterial / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D013270:Stomach / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D003603:Cytotoxins; D012329:RNA, Bacterial; D012333:RNA, Messenger; C080866:cagA protein, Helicobacter pylori; D049453:Luciferases, Bacterial; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3