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.
Highlights
Esophageal cancer is the seventh most common cancer worldwide and ranks sixth in terms of cancer mortality (Bray et al, 2018)
Thirty-nine ferroptosis-related genes (FRGs) were significantly associated with the prognosis of Esophageal squamous cell carcinoma (ESCC) (p < 0.1)
The heatmap showed that SRC, FADS2, GLUD1, POLG, ANO6, SLC2A6 and ANGPTL7 were highly expressed, while PTGS2, arachidonate lipoxygenase E3 (ALOXE3), and SLC38A1 were downregulated in high-risk cases (Figure 2D)
Summary
Esophageal cancer is the seventh most common cancer worldwide and ranks sixth in terms of cancer mortality (Bray et al, 2018). Due to advancements in high-throughput technologies, such as microarray and RNA sequencing, gene expression profiling has been widely used to discover molecular biomarkers associated with the phenotype or prognosis of cancer (Zhan et al, 2016). Multigene signatures, such as Oncotype DX for breast cancer or ColoPrint chips for colon cancer, have proven to be of great prognostic value for cancers, and the described signatures can be employed to guide the prognostic evaluation, treatment and management of cancers (Birnbaum et al, 2017). There is an urgent need to identify key molecular biomarkers related to the prognosis of ESCC
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