Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Apr 15, 2025; 17(4): 103843
Published online Apr 15, 2025. doi: 10.4251/wjgo.v17.i4.103843
Nitric oxide synthase 1 inhibits the progression of esophageal cancer through interacting with nitric oxide synthase 1 adaptor protein
Zi-Wei Xiao, Ying-Chao Zeng, Lin-Tao Ji, Jia-Tao Yuan, Lin Li
Zi-Wei Xiao, Ying-Chao Zeng, Lin-Tao Ji, Jia-Tao Yuan, Lin Li, College of Medical, Hunan Normal University, Changsha 410081, Hunan Province, China
Author contributions: Li L and Xiao ZW designed the experiments, wrote the manuscript, and revised it; Zeng YC, Ji LT, and Yuan JT performed the experiments. All authors contributed to the analysis of the results and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81000201.
Institutional review board statement: This study does not involve any human experiments.
Institutional animal care and use committee statement: All animal experiments were approved by the Animal Ethical and Welfare Committee of Guangzhou Miles Biosciences, (No. MIS20230070).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Lin Li, Associate Professor, College of Medical, Hunan Normal University, No. 36 Lushan Road, Changsha 410081, Hunan Province, China. 18529482372@163.com
Received: December 3, 2024
Revised: January 22, 2025
Accepted: February 17, 2025
Published online: April 15, 2025
Processing time: 113 Days and 10.2 Hours
Abstract
BACKGROUND

Esophageal cancer (ESCA) is among the most prevalent and lethal tumors globally. While nitric oxide synthase 1 (NOS1) is recognized for its important involvement in various cancers, its specific function in ESCA remains unclear.

AIM

To explore the potential role and underlying mechanisms of NOS1 in ESCA.

METHODS

Survival rates were analyzed using GeneCards and Gene Expression Profiling Interactive Analysis. The effects and mechanisms of NOS1 on ESCA cells were evaluated via the Cell Counting Kit-8 assay, scratch assay, Transwell assay, flow cytometry, quantitative polymerase chain reaction, western blotting, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining. The protein interaction network was used to screen the interacting proteins of NOS1 and validate these interactions through co-immunoprecipitation and dual luciferase assays. Additionally, a nude mouse xenograft model was established to evaluate the effect of NOS1 in vivo.

RESULTS

The survival rate of patients with ESCA with high NOS1 expression was higher than that of patients with low NOS1 expression. NOS1 expression in ESCA cell lines was lower than that in normal esophageal epithelial cells. Overexpression of NOS1 (oe-NOS1) inhibited proliferation, invasion, and migration abilities in ESCA cell lines, resulting in decreased autophagy levels and increased apoptosis, pyroptosis, and ferroptosis. Protein interaction studies confirmed the interaction between NOS1 and NOS1 adaptor protein (NOS1AP). Following oe-NOS1 and the silencing of NOS1AP, levels of P62 and microtubule-associated protein 1 light chain 3 beta increased both in vitro and in vivo. Furthermore, the expression levels of E-cadherin, along with the activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT), were inhibited in ESCA cell lines.

CONCLUSION

NOS1 and NOS1 proteins interact to suppress autophagy, activate the PI3K/AKT pathway, and exert anti-cancer effects in ESCA.

Keywords: Nitric oxide synthase 1; Nitric oxide synthase 1 adaptor protein; Autophagy; Phosphatidylinositol 3-kinase/protein kinase B pathway; Esophageal cancer

Core Tip: Nitric oxide synthase 1 (NOS1) inhibits the proliferation, metastasis, apoptosis, pyroptosis, and ferroptosis of esophageal cancer (ESCA) cells; enhances the autophagy; and effectively delays the onset of ESCA in a nude mouse xenograft model. Mechanistically, NOS1 interacts with the NOS1 adaptor protein, inhibiting the activation of the phosphatidylinositol 3-kinase/protein kinase B pathway. Both in vitro and in vivo studies suggest that NOS1 is a potential therapeutic target for ESCA.