Development and Validation of a Ferroptosis-Related Gene Signature and Nomogram for Predicting the Prognosis of Esophageal Squamous Cell Carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with high mortality and poor prognosis. Ferroptosis is a newly discovered form of cell death induced by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids (PUFAs). However, the prognostic value of ferroptosis-related genes (FRGs) for ESCC remains unclear. Based on the ESCC dataset from the Gene Expression Omnibus (GEO) database, we identified 39 prognostic FRGs through univariate Cox regression analysis. After LASSO regression and multivariate Cox regression analyses, a multigene signature based on 10 prognostic FRGs was constructed and successfully divided ESCC patients into two risk groups. Patients in the low-risk group showed a significantly better prognosis than patients in the high-risk group. In addition, we combined the risk score with clinical predictors to construct a nomogram for ESCC. The predictive ability of the nomogram was further verified by ROC curves and calibration plots in both the training and validation sets. The predictive power of the nomogram was demonstrated to be better than that of either the risk score or clinical variable alone. Furthermore, functional analysis revealed that the 10-FRG signature was mainly associated with ferroptosis, differentiation and immune response. Connectivity map analysis identified potential compounds capable of targeting FRGs in ESCC. Finally, we demonstrated the prognostic value of SRC gene in ESCC using the clinical samples and found that SRC inhibition sensitized ESCC cells to ferroptosis inducers by in vitro experiments. In conclusion, we identified and verified a 10-FRG prognostic signature and a nomogram, which provide individualized prognosis prediction and provide insight into potential therapeutic targets for ESCC.

Glycolysis-Related LINC02432/Hsa-miR-98–5p/HK2 Axis Inhibits Ferroptosis and Predicts Immune Infiltration, Tumor Mutation Burden, and Drug Sensitivity in Pancreatic Adenocarcinoma

“…NAD(P)H: ubiquinone oxidoreductase-1 (NQO1) functioned as a CoQ oxidoreductase and mitochondrial ROS inhibitor and has been demonstrated to suppress ferroptosis ( Sun et al, 2016 ; Peng et al, 2022 ). Studies have shown that the activation of SRC proto-oncogene non-receptor tyrosine kinase (SRC) can inhibit cancer cell ferroptosis by inhibiting the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) ( Brown et al, 2017 ; Ye et al, 2021 ). This further suggested the regulatory role of LINC02432/hsa-miR-98–5p/HK2 axis on ferroptosis inhibition.…”

Ferroptosis and its emerging role in esophageal cancer

“…On this basis, the researcher selected SLC38A1 with noticeable expression difference to further explore its influence on the proliferation and migration of ESCC cells and finally concluded that SLC38A1 promoted the proliferation and migration of ESCC cells ( Song et al, 2021 ); Ye et al identified SRC, FADS2, GLUD1, POLG, ANO6, SLC2A6, PTGS2, ALOXE3, etc. ( Ye et al, 2021 ); Zhao et al identified six FRGs with prognostic value in 112 ESCC samples ( Zhao M. et al, 2022 ). Among them, the expressions of PRNP, SLC3A2, SLC39A8, and SLC39A14 were negatively correlated with the prognosis of ESCC patients, while the expressions of ATP6V0A1 and LCN2 were the opposite.…”

Development of a Novel Prognostic Model for Esophageal Squamous Cell Carcinoma: Insights into Immune Cell Interactions and Drug Sensitivity

“…However, this eld of study has not seen signi cant progress in esophageal cancer, largely due to insu ciencies in data sets. In existing studies, researchers have utilized multiple datasets and examined genes associated with signal pathways, including ferroptosis [6,7] , epithelial-mesenchymal transition [8], and autophagy-related genes [9]. Nevertheless, due to various factors such as lack of data sets, inferior quality of data sets, and incompleteness of research schemes, the established gene signatures have not shown substantive discriminative capability in prognosticating for ESCC patients, with AUC values often distributed around 0.7.…”