PGE2 up-regulates vascular endothelial growth factor expression in MKN28 gastric cancer cells via epidermal growth factor receptor signaling system

Aim: 1) To evaluate the effect of prostaglandin E-2 (PGE(2)) on the regulation of vascular endothelial growth factor (VEGF) expression in gastric MKN28 cells, and 2) to investigate the role of the epidermal growth factor receptor (EGFR) signal transduction pathway in any effect exerted by PGE(2) on VEGF expression. Methods: MKN28 cells were incubated with the vehicle (control) or with PGE(2) in the presence or absence of AG1478, a selective inhibitor of EGFR tyrosine kinase, or PD098059, a selective inhibitor of the kinase responsible for ERK2 phosphorylation (mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK)). Real-time quantitative polymerase chain reaction and Western blot analysis were used to evaluate VEGF mRNA and protein expression. The activity of EGFR and ERK2 was measured by Western blot analysis. Results: PGE(2) significantly up-regulated VEGF mRNA and protein expression and increased the activation of EGFR and ERK2. Incubation of MKN28 cells with AG1478 significantly reduced PGE(2)-induced EGFR activity, ERK2 activity, and VEGF mRNA and protein expression. Meanwhile, incubation of MKN28 with PD098059 reduced PGE(2)-induced ERK2 activity and VEGF mRNA and protein expression, but had no effect on EGFR activity. Conclusion: Our data suggested that PGE(2) upregulates VEGF expression in gastric cancer cells via transactivation of EGFR-MAPK signaling pathways, which may be mechanisms underlying the contribution of COX-2 to tumor angiogenesis in gastric cancer.