4843

NOS2

nitric oxide synthase 2, inducible;NOS2;nitric oxide synthase 2, inducible

NOS type II|NOS, type II|hepatocyte NOS|inducible NO synthase|inducible NOS|nitric oxide synthase 2A (inducible, hepatocytes)|nitric oxide synthase, inducible|nitric oxide synthase, macrophage|peptidyl-cysteine S-nitrosylase NOS2

17q11.2

protein-coding

BACKGROUND: The growth and metastasis of tumors depend on the development of an adequate blood supply via angiogenesis. Recent studies indicate that the inducible nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF) and the tumor suppressor p53 are fundamental play-markers of the angiogenic process. Overexpression of iNOS and VEGF has been shown to induce angiogenesis in tumors. P53 suppresses angiogenesis by down-regulating VEGF and iNOS. The correlation of expression of p53, VEGF and iNOS and clinical features in gastric carcinogenesis, however, has not been well characterized. METHODS: The expression of p53, iNOS and VEGF in gastric precancerous and cancerous lesions and its relation with the clinical features was determined with immunohistochemistry (avidin-biotin-peroxidase complex method) on 55 randomly selected GC patients and 60 symptom-free subjects from the mass survey in the high-incidence area for GC in Henan, northern China. RESULTS: The positive immunostaining rates for p53, iNOS and VEGF in gastric carcinomas were 51%, 44% and 51%, respectively, and correlated well with TNM stages, but did not show significant difference among the groups with different degrees of gastric wall invasion depth by GC. A positive immunostaining reaction for the iNOS protein was significantly correlated with lymph node metastasis (p = 0.019; Spearman correlation coefficient). P53 protein accumulation was higher in the poorly-differentiated gastric carcinoma than in well-differentiated one. In gastric biopsies, no positive immunostaining was observed for p53, iNOS and VEGF in the histologically normal tissue and chronic superficial gastritis (CSG). However, p53, iNOS and VEGF positive immunostaining was observed in the tissues with different severities of lesions of chronic atrophic gastritis (CAG), intestinal metaplasia (IM) and dysplasia (DYS), and the positive rates increased with the lesion progression from CAG to IM to DYS. A high coincidental positive and negative immunostaining rate for p53, iNOS and VEGF was observed both in biopsy samples with CAG, IM and DYS from the symptom-free subjects and in gastric cancer tissue from the GC patients. CONCLUSIONS: The present results indicated that p53 protein accumulation and increased expression of iNOS and VEGF might be responsible for gastric carcinogenesis and tumor aggressiveness of gastric cancer.

AIM: To investigate the relationship between the expression of inducible nitric oxide synthase(iNOS),vascular endothelial growth factor(VEGF),the microvascular density (MVD) and the pathological features and clinical staging of gastric cancer. METHODS: Immunohistochemical staining was used for detecting the expression of iNOS and VEGF in 46 resected specimens of gastric carcinoma; the monoclonal antibody against CD34 was used for displaying vascular endothelial cells, and MVD was detected by counting of CD34-positive vascular endothelial cells. RESULTS: Of 46 resected specimens of gastric carcinoma,the rates of expressions of iNOS and VEGF were 58.70% and 76.09%, respectively,and MVD averaged 55.59+/-19.39.Judged by the standard TNM criteria, the rate of expression of iNOS in stage IV (84.46%) was higher than those in stage I,II, III(Fish exact probabilities test, P=0.019,0.023 and 0.033,respectively);the rates of expression of VEGF in stage III,IV (76.0%,92.31%,respectively) were higher than those in stage I,II (Fish exact probabilities test, P=0.031,0.017,0.022 and 0.019). MVDs in stage III,IV(64.72+/-14.96,67.09+/-18.29,respectively) were higher than those in stage I,II(t=2.378,4.015,2.503 and 2.450, P<0.05,P<0.001,P<0.001, P<0.05,respectively). In 37 gastric carcinoma specimens with lymph node metastasis, MVD(68.69+/-18.07) and the rates of expression of iNOS and VEGF(70.27%,83.78%,respectively) were higher than those in the specimens with absence of metastasis (t=2.205, chi(2)=6.3587, chi(2)=6.2584, P<0.01, P<0.05, P<0.05, respectively). MVD and the expressions of iNOS and VEGF were not correlated to the location,size or grade of tumor,nor with the depth of invasion of tumor; MVDs in the positive iNOS and VEGF specimens(59.88+/-18.02,58.39+/-17.73, respectively) were higher than those in the negative iNOS and VEGF specimens (chi(2)=6.3587 and 6.1574, P<0.05, P<0.05,respectively);thus the expressions of iNOS and VEGF was correlated to MVD,but the expression of iNOS was not correlated to that of VEGF. In addition,of the 46 surviving patients, the 5-year survival rate of patients with positive iNOS or VEGF tumors was significantly less than that of patients with negative iNOS-or VEGF tumors(chi(2)=4.3842 and 5.4073, P<0.05, P<0.05, respectively). CONCLUSION: The expressions of iNOS and VEGF are closely related to tumor angiogenesis,and are involved in the advancement and the lymph node metastasis; thus MVD and the expressions of iNOS and VEGF may serve indexes for evaluating staging of gastric carcinoma and forecasting its risk of metastasis, which will help establish a comprehensive therapeutical measure of post-operative patients and provide a new approach to tumor therapy.

Increased nitric oxide synthase expression plays a key role in tumor progression. To examine inducible nitric oxide synthase expression and its correlation with clinical variables, such as tumor progression, angiogenesis, lymphangiogenesis, and prognosis in gastric cancer, we studied inducible nitric oxide synthase expression in gastric cancer samples from 211 patients with 5-year follow-up. CD105 and D2-40 were adopted as biomarkers for tumor angiogenesis and lymphangiogenesis, respectively. Inducible nitric oxide synthase staining was mainly found in the cytoplasm of gastric cancer tumor cells. Positive inducible nitric oxide synthase immunoreactivity was seen in 54.03% of gastric cancer specimens, which was correlated with lymph node metastasis, vascular invasion, distant metastasis, and TNM stage. Compared with inducible nitric oxide synthase negative patients, inducible nitric oxide synthase-positive patients had significantly shorter survival times and higher microvessel density and lymphatic vessel density. Intratumor and peritumor blood microvessel density and lymphatic vessel density correlated with inducible nitric oxide synthase expression (Spearman rho test, P < .05). We conclude that inducible nitric oxide synthase expression correlates with lymph node metastasis, vascular invasion, distant metastasis, TNM stage, and poor survival rate in gastric cancer. We propose that synthesized inducible nitric oxide synthase increases angiogenesis, and lymphangiogenesis thus promotes tumor progression. Inducible nitric oxide synthase expression may be a good biomarker for poor prognosis in gastric cancer.

BACKGROUND: The inducible nitric oxide synthase (iNOS) is associated with inflammatory processes and cancer formation through production of nitric oxide (NO). However, the clinical importance of the expression of iNOS in oral cancer remains unclear. In the present study, we examined whether up-regulation of the iNOS gene can affect growth and metastasis of an oral cancer cell line (B88t cell) in vitro and in vivo. MATERIALS AND METHODS: We constructed an expression vector containing sense-oriented murine iNOS cDNA with pcDNA3.1. We transfected B88t cells with the sense expression vector to up-regulate the expression of the iNOS gene in the sense transfectants. RESULTS: The expression of iNOS protein was up-regulated in the sense transfectants and that up-regulation of the iNOS gene exerted a growth inhibitory effect on B88t cells in vitro and in vivo. Moreover, up-regulation of the iNOS gene markedly inhibited the migration of cancer cells in a Boyden chamber. Furthermore, up-regulation of the iNOS gene dramatically inhibited metastases to the cervical lymph node in vivo. CONCLUSION: These findings suggest that up-regulation of the iNOS gene may suppress the tumorigenicity and metastasis of oral cancer cells.