Expression of endothelial nitric oxide synthase correlates with the angiogenic phenotype of and predicts poor prognosis in human gastric cancer

Background. Angiogenesis is a critical aspect of cancer biology and is subject to regulation by multiple molecular pathways. We evaluated the expression of nitric oxide synthase (NOS) III and its relationship with the angiogenic phenotype and expression of the transcription factor Sp1, as well as their effect on survival in patients with gastric cancer. Methods. The NOS III expression level and tumor microvessel density (MVD) status were determined via immunohistochemistry, using archived tissue specimens from 86 resected gastric cancer cases; these findings were then correlated with Sp1 expression and clinicopathological features. Results. NOS III protein expression was significantly higher in both primary tumors and lymph node metastases than in normal gastric mucosa. In primary tumors, NOS III expression correlated highly with Sp1 expression (P = 0.001) and MVD status (P = 0.001). Patients with strong Sp1 expression were more likely to have strong NOS III expression (15 times) and a high MVD (7 times) than were those with negative Sp1 expression. In univariate survival analyses, strong NOS III expression (P = 0.042), strong Sp1 expression (P = 0.007), and a high MVD (P = 0.036) were associated with worse survival. However, when patients' NOS III and Sp1 expression levels, MVD status, disease stage, completeness of resection, Lauren's classification, and age were entered in a Cox proportional hazards model, only strong NOS III (P = 0.019) and Sp1 expression (P = 0.029) and advanced disease stage (P = 0.006) were independently prognostic of poor survival. Conclusion. Our results indicated that the expression of NOS III, a potential downstream effector of Sp1, may play an important role in tumor angiogenesis and aggressiveness in gastric cancer.