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
- 1Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- 2Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, TN, USA
- Correspondence to:
Dr S Keates
Division of Gastroenterology, Dana 601, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA;
- Accepted 28 April 2005
- Revised 11 April 2005
- Published Online First 29 April 2005
Background and aims: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.
Methods and 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.
- Egr-1, early growth response gene 1
- EGFR, epidermal growth factor receptor
- ERK, extracellular regulated kinases
- MAP kinases, mitogen activated protein kinases
- PAI, pathogenicity island
- cag, cytotoxin associated genes
- PMA, phorbol-12-myristate-13-acetate
- MOI, multiplicity of infection
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- PCR, polymerase chain reaction
- EMSA, electrophoretic mobility shift assay
- JNK, c-Jun N-terminal kinase
Conflict of interest: None declared.
Published online first 29 April 2005