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Background:   NOS3  (endothelial NOS,  eNOS ) is a member of the nitric oxide synthase (NOS) enzyme family, mainly participating in nitric oxide (NO) generation.  NOS3  has been reported to inhibit apoptosis and promote angiogenesis, proliferation, and invasiveness. However, the expression pattern of  NOS3  and its diagnostic and prognostic potential has not been investigated in a pan-cancer perspective.   Methods:  Data from the Genotype-Tissue Expression (GTEx), the Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE), and the Cancer Therapeutics Response Portal (CTRP) were employed and  NOS3  expression was comprehensively analyzed in normal tissues, cancer tissues, and cell lines. Immunohistochemical staining of tissue sections were used to validate the prognostic role of  NOS3  in gastric cancer patients. GSVA and GSEA analyses were performed to investigate signaling pathways related to  NOS3  expression.   Results:  In normal tissues,  NOS3  was expressed highest in the spleen and lowest in the blood.  NOS3  expression was increased in stomach adenocarcinoma (STAD) and significantly associated with poor prognosis of patients. Immunohistochemical staining validated that  NOS3  was an independent prognostic factor of gastric cancer. Several canonical cancer-related pathways were found to be correlated with  NOS3  expression in STAD. The expression of NOS3 was related to the response to QS-11 and brivinib in STAD.   Conclusions:   NOS3  was an independent prognostic factor for patients with STAD. Increased expression of  NOS3  influenced occurrence and development of STAD through several canonical cancer-related pathways. Drug response analysis reported drugs to suppress NOS3. NOS3 might be a novel target for gastric cancer treatment.

Pan-Cancer Analysis of NOS3 Identifies Its Expression and Clinical Relevance in Gastric Cancer