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Helicobacter pylori VacA Toxin Up-Regulates Vascular Endothelial Growth Factor Expression in MKN 28 Gastric Cells through an Epidermal Growth Factor Receptor-, Cyclooxygenase-2-dependent Mechanism¹

Dipartimento di Internistica Clinica e Sperimentale-Cattedra di Gastroenterologia, Seconda Università di Napoli, Napoli [C. T., B. A. M., C. D. V. B., M. R.]; Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università Federico II, 80131 Napoli [R. C., G. T., F. C.]; Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II, Napoli [R. Z.]; and Istituto di Fisiologia Umana, Università di Pavia [V. R.], Italy

Purpose: Helicobacter pylori causes gastric damage and is involved in gastric carcinogenesis. Vascular endothelial growth factor (VEGF) plays a major role in gastric mucosa repair and is overexpressed in gastric cancer. We investigated: (a) whether H. pylori, and in particular H. pylori VacA toxin, affected VEGF expression in gastric epithelial cells in culture; and (b) the signal transduction pathway involved in any effect exerted by H. pylori.

Experimental Design: MKN-28 cells were incubated with uninoculated BCF (control) or with BCF obtained from VacA-producing wild-type H. pylori 60190 strain or from its isogenic mutant 60190:v1, specifically lacking vacA gene in the presence or absence of ZD 1839, a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, PD098059, a selective inhibitor of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase, the kinase responsible for ERK phosphorylation, or SC-236, a selective inhibitor of cyclooxygenase (COX)-2 for 24–48 h.

Results: (a) Toxigenic H. pylori up-regulated VEGF mRNA and protein expression and caused a 2.5-fold increase in VEGF release compared with control, whereas nontoxigenic H. pylori did not; (b) H. pylori VacA toxin-induced up-regulation of VEGF was counteracted by selective inhibition of EGFR tyrosine kinase; (c) toxigenic H. pylori activated the ERK/MAP kinase cascade, and inhibition of MAP kinase activation counteracted H. pylori-induced VEGF up-regulation; (d) toxigenic H. pylori up-regulated COX-2 expression, and this effect was counteracted by blockade of EGFR tyrosine kinase; and (e) COX-2 selective inhibition counteracted H. pylori-induced up-regulation of VEGF.

Conclusion: (a) H. pylori up-regulates VEGF expression in gastric epithelial cells; and (b) this effect is specifically related to VacA toxin and seems to depend on the activation of an EGFR-, MAP kinase-, and COX-2-mediated pathway.

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