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.


CONCLUSIONS
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.
Wang
Liwei
L
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Shi
Gary G
GG
Yao
James C
JC
Gong
Weida
W
Wei
Daoyan
D
Wu
Tsung-Teh
TT
Ajani
Jaffer A
JA
Huang
Suyun
S
Xie
Keping
K
D000367:Age Factors; D000368:Aged; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D016329:Sp1 Transcription Factor / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*
D016329:Sp1 Transcription Factor; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III