Development of a prognostic model based on ferroptosis-related genes for colorectal cancer patients and exploration of the biological functions of NOS2 in vivo and in vitro

Hongming Li; Xiaochuang Feng; Yong Hu; Junjiang Wang; Chengzhi Huang; Xueqing Yao

doi:10.3389/fonc.2023.1133946

Development of a prognostic model based on ferroptosis-related genes for colorectal cancer patients and exploration of the biological functions of NOS2 in vivo and in vitro

Front Oncol. 2023 Jun 6:13:1133946. doi: 10.3389/fonc.2023.1133946. eCollection 2023.

Authors

Hongming Li^{1

2

3}, Xiaochuang Feng³, Yong Hu², Junjiang Wang^{1

2}, Chengzhi Huang⁴, Xueqing Yao^{1

2}

Affiliations

¹ The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
² Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
³ Department of Colorectal Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China.
⁴ School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, Guangdong, China.

Abstract

Background: Ferroptosis is involved in many malignant tumors and has been implicated in important mechanisms of colorectal cancer (CRC) suppression. However, the prognostic and predictive values of the ferroptosis activation pattern in CRC patients have not been noted. Here, we aimed to construct and validate a prediction model based on ferroptosis-related genes (FRGs) for CRC patients and investigated the expression pattern and biological function of the most significantly altered gene.

Methods: A total of 112 FRGs were obtained from the FerrDb website, and the clinical characteristics of 545 CRC patients and their global gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Survival-related FRGs were identified by Cox proportional hazards regression analysis. Finally, the expression pattern and biological function of NOS2, the most implicated gene was explored in vitro and in vivo.

Results: The prediction model was established based on 8 FRGs. Patients in the high- or low-risk group were stratified based on the median risk value calculated by our model, and patients in the high-risk group experienced poor overall survival (p<0.01). Further validation demonstrated that the FRG model acted as an independent prognostic indicator for CRC patients (HR=1.428, 95% CI, 1.341-1.627; p<0.001). The area under the receiver operating characteristic (ROC) curve (AUC) for 5-year survival was 0.741. NOS2 was one of the most significantly affected FRGs and was highly expressed in malignant tissue, but it inhibited tumor growth and induced tumor cell death in vitro and in vivo, possibly by repressing the NF-κB pathway.

Conclusion: Our study revealed that FRGs have potential prognostic value in CRC patients and that NOS2 suppresses tumor progression, providing a novel therapeutic target for CRC treatment based on ferroptosis.

Keywords: NOS2; colorectal cancer; ferroptosis; gene; prognostic model.

Grants and funding

This study was supported by Leading Innovation Specialist Support Program of Guangdong Province, the Science and Technology Planning Project of Ganzhou (No. 202101074816), Scientific Research Project of Guangdong Provincial Traditional Chinese Medicine Bureau (No. 20211155), Medical Scientific Research Foundation of Guangdong Province (No. A2022305), National Key Clinical Specialty Construction Project (2021–2024, No. 2022YW030009), National Natural Science Foundation of China (No. 82260501), the Science and Technology Planning Project of Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences, No. DFJH201913), CSCO-Roche Cancer Research Foundation (No. Y-2019Roche-190) and CSCO-Haosen Research Foundation (No.YHS2019/2–050).