Published online May 15, 2024. doi: 10.4251/wjgo.v16.i5.2018
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
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.
To identify coregulated differentially expressed genes among ferroptosis-related genes (FRGs) in GC patients and develop a ferroptosis-related prognostic model with discrimination ability.
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.
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.
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.
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.