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<p>Abstract</p> <p>Background</p> <p>Vascular endothelial growth factor (VEGF) expression is up-regulated via a cyclooxygenase-2 (COX-2)-dependent mechanism in non-small cell lung cancer (NSCLC), but the specific signaling pathway involved is unclear. Our aim was to investigate the signaling pathway that links COX-2 with VEGF up-regulation in NSCLC.</p> <p>Material and methods</p> <p>COX-2 expression in NSCLC samples was detected immunohistochemically, and its association with VEGF, microvessel density (MVD), and other clinicopathological characteristics was determined. The effect of COX-2 treatment on the proliferation of NSCLC cells (A549, H460 and A431 cell lines) was assessed using the tetrazolium-based MTT method, and VEGF expression in tumor cells was evaluated by flow cytometry. COX-2-induced VEGF expression in tumor cells was monitored after treatment with inhibitors of protein kinase C (PKC), PKA, prostaglandin E2 (PGE₂), and an activator of PKC.</p> <p>Results</p> <p>COX-2 over-expression correlated with MVD (<it>P </it>= 0.036) and VEGF expression (<it>P </it>= 0.001) in NSCLC samples, and multivariate analysis demonstrated an association of VEGF with COX-2 expression (<it>P </it>= 0.001). Exogenously applied COX-2 stimulated the growth of NSCLCs, exhibiting EC₅₀values of 8.95 × 10^-3, 11.20 × 10^-3, and 11.20 × 10^-3μM in A549, H460, and A431 cells, respectively; COX-2 treatment also enhanced tumor-associated VEGF expression with similar potency. Inhibitors of PKC and PGE₂attenuated COX-2-induced VEGF expression in NLCSCs, whereas a PKC activator exerted a potentiating effect.</p> <p>Conclusion</p> <p>COX-2 may contribute to VEGF expression in NSCLC. PKC and downstream signaling through prostaglandin may be involved in these COX-2 actions.</p>