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

Dan Zou,Yi Yang,Zhitao Jing,Yu Tang,Zi Jin,Jinpeng Zhou,Yang Chen,Fei Lv,Ye Zhang,Yang Jiang,Zhi Li,Yanju Ma,Chunjiao Yang,Jincheng Song

doi:10.3389/fonc.2021.592761

Abstract

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.

Highlights

NOS3 is a member of the nitric oxide synthase (NOS) enzyme family, which is a cluster of catalytic enzymes that mainly participate in nitric oxide (NO) generation [1]
NOS3 expression in different cell lines was checked and the results showed that cell lines from STAD and COAD were the top two cell lines expressing the highest levels of NOS3 mRNA, and cell lines from nerve system tissues (e.g., GBM and neuroblastoma) and bone tissues expressed relatively lower NOS3 mRNA (Figure 2A)
We found that among the six tumor types expressed higher NOS3 level, NOS3 mRNA was related to a worse prognosis in patients with STAD (Figure 4B)

Summary

Introduction

NOS3 (endothelial NOS, eNOS) is a member of the nitric oxide synthase (NOS) enzyme family, which is a cluster of catalytic enzymes that mainly participate in nitric oxide (NO) generation [1]. NOS3 protein was initially found to participate in NO generation, mainly in endothelial cells, and is associated with cardiovascular diseases such as hypertension, atherosclerosis, and diabetes mellitus [5]. It was found to promote angiogenesis via PI3K/Akt/mTOR pathway, and enhance the migration and invasion via NOS3-NO-sGC-cGMP signaling in breast cancer cells [12, 13]. NOS3 participated in the enhancement of Taxol chemosensitivity with astragaloside IV treatment in breast cancer as a downstream target of caveolin-1 [25]. These studies suggest that NOS3 may perform multiple functions depending on different tumor types, and genetic background. The expression pattern of NOS3 and its diagnostic and prognostic potential has not been investigated in a pan-cancer perspective

Methods

Results

Conclusion