Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. May 15, 2024; 16(5): 2018-2037
Published online May 15, 2024. doi: 10.4251/wjgo.v16.i5.2018
Predictive model using four ferroptosis-related genes accurately predicts gastric cancer prognosis
Li Wang, Wei-Hua Gong
Li Wang, Department of Emergency, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
Wei-Hua Gong, Department of Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
Author contributions: Wang L contributed data compilation, formal analysis, writing-original version; Gong WH contributed methodology, writing original draft. conceptualization, obtaining funding, mentoring, writing-review and editing.
Institutional review board statement: The protocol of the study was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital Zhejiang University School of Medicine (2023-0177).
Institutional animal care and use committee statement: This study and included experimental procedures were approved by the institutional animal care and use committee of Zhejiang Chinese Medicine University (No. IACUC-20230410-21). All animal housing and experiments were conducted in strict accordance with the institutional guidelines for care and use of laboratory animals.
Informed consent statement: All participants signed informed consent forms.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data analyzed in this study are available in the cancer genome atlas database (https://portal.gdc.cancer.gov/); FerrDb Database (http://www.zhounan.org/ferrdb/current/). And the GSE datas downland from below address: (GSE99553: https://www.ncbi.nlm.nih.gov/geo/geo2r/?acc=GSE99553), (GSE84426: https://www.ncbi.nlm.nih.gov/geo/geo2r/?acc=GSE84426). And the experimental data supporting the findings of this study are available within the article. The Supplementary Dataset File was the WB result of Fig 7C and Fig 8E.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Wei-Hua Gong, PhD, Researcher, Department of Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310052, Zhejiang Province, China. weihuagong@zju.edu.cn
Received: October 21, 2023
Peer-review started: October 21, 2023
First decision: January 25, 2024
Revised: January 31, 2024
Accepted: March 8, 2024
Article in press: March 8, 2024
Published online: May 15, 2024
Processing time: 201 Days and 12.2 Hours
Abstract
BACKGROUND

Gastric cancer (GC) is a common malignancy of the digestive system. According to global 2018 cancer data, GC has the fifth-highest incidence and the third-highest fatality rate among malignant tumors. More than 60% of GC are linked to infection with Helicobacter pylori (H. pylori), a gram-negative, active, microaerophilic, and helical bacterium. This parasite induces GC by producing toxic factors, such as cytotoxin-related gene A, vacuolar cytotoxin A, and outer membrane proteins. Ferroptosis, or iron-dependent programmed cell death, has been linked to GC, although there has been little research on the link between H. pylori infection-related GC and ferroptosis.

AIM

To identify coregulated differentially expressed genes among ferroptosis-related genes (FRGs) in GC patients and develop a ferroptosis-related prognostic model with discrimination ability.

METHODS

Gene expression profiles of GC patients and those with H. pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. The FRGs were acquired from the FerrDb database. A ferroptosis-related gene prognostic index (FRGPI) was created using least absolute shrinkage and selection operator–Cox regression. The predictive ability of the FRGPI was validated in the GEO cohort. Finally, we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues.

RESULTS

Four hub genes were identified (NOX4, MTCH1, GABARAPL2, and SLC2A3) and shown to accurately predict GC and H. pylori-associated GC. The FRGPI based on the hub genes could independently predict GC patient survival; GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group. The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression. Moreover, the gene expression levels of common immune checkpoint proteins dramatically increased in the high-risk subgroup of the FRGPI cohort. The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane. The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner.

CONCLUSION

In this study, we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.

Keywords: Ferroptosis; Gastric cancer; Helicobacter pylori infection; Immune checkpoint protein; Prognostic model; Ferroptosis-related gene prognostic index

Core Tip: This study aimed to develop a prognostic model based on coregulated differentially expressed genes among ferroptosis-related genes (FRGs) in gastric cancer (GC). Gene expression profiles from GC patients and those with Helicobacter pylori-associated GC were analyzed, along with FRGs obtained from the FerrDb database. The resulting ferroptosis-related gene prognostic index (FRGPI), based on four hub genes (NOX4, MTCH1, GABARAPL2, and SLC2A3), accurately predicted GC patient survival. High-risk individuals had significantly worse overall survival, and the FRGPI was associated with disease progression and increased expression of immune checkpoint proteins. These findings provide insights into GC prognosis and immunotherapy efficacy.