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. 2022 Mar 6;13(5):1611-1622.
doi: 10.7150/jca.68568. eCollection 2022.

Identification and analysis of a prognostic ferroptosis and iron-metabolism signature for esophageal squamous cell carcinoma

Mengnan Zhao  1 , Ming Li  1 , Yuansheng Zheng  1 , Zhengyang Hu  1 , Jiaqi Liang  1 , Guoshu Bi  1 , Yunyi Bian  1 , Qihai Sui  1 , Cheng Zhan  1 , Miao Lin  1 , Qun Wang  1
Affiliations

Identification and analysis of a prognostic ferroptosis and iron-metabolism signature for esophageal squamous cell carcinoma

Mengnan Zhao et al. J Cancer. .

Abstract

Background: The role of ferroptosis in esophageal squamous cell carcinoma (ESCC) is still unclear. Methods: The association of iron metabolism and ferroptosis-related genes with the prognosis, copy number variation (CNV), TMB, and immune cell infiltration of ESCC was explored using data from the GEO and TCGA database and validated by immunofluorescence in 112 ESCC patients from our center. The potential anti-cancer drugs and compounds from the GDSC and the Connectivity Map database were also screened. Results: A total of 117 iron metabolism and ferroptosis-related genes were identified. We found the expressions of PRNP, SLC3A2, SLC39A8, and SLC39A14 negatively related to the prognosis of ESCC patients, while ATP6V0A1 and LCN2 were opposite, which was validated in 112 ESCC samples from our center. And a prognostic signature was constructed based on their expressions and Cox regression coefficient (β). The low-score group exhibited a significantly worse OS. Besides, analysis of 179 ESCC samples from GSE53625 revealed that patients of poorly differentiation, more than 60 years, T4 stage, advanced N stage, advanced stage, and adjuvant therapy also exhibited a significantly shorter OS, based on which a nomogram to predict the OS was established. Moreover, the low-score group exhibited significantly higher CNV and TMB and more frequent mutations of TP53, MUC16, and NOTCH1. Higher proportion of Macrophages M2, and lower proportion of T cells follicular helper were observed in the low-score group. We discovered that AZD7762, Sunitinib, Cytarabine, Docetaxel, Vinblastine, and Elesclomol exhibited lower IC50 in the low-score group. And 20 potential compounds were identified from the CMap database. Conclusions: Six iron metabolism and ferroptosis-related genes were associated with the prognosis, CNV, TMB, and immune cell infiltration of ESCC. Some potential anti-cancer drugs and compounds may be helpful for OS.

Keywords: Connectivity Map database; GDSC database; GEO database; TCGA database; TMB; esophageal squamous cell carcinoma.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Forest map (A) and Kaplan-Meier curves of PRNP (B), SLC39A8 (C), LCN2 (D), ATP6V0A1 (E), SLC3A2 (F), and SLC39A14 (G) based on the TCGA database.
Figure 2
Figure 2
Relative mRNA expressions (A) and lipid peroxidation (B) after transfection with siRNAs in KYSE150 cells.
Figure 3
Figure 3
Kaplan-Meier curve (A) and AUC of time-dependent ROC curves (B) of ESCC patients in the low and high score group based on the TCGA database and Kaplan-Meier curve (C), nomogram (E) and calibration plots (D, F) of ESCC patients from the GSE53625 dataset.
Figure 4
Figure 4
Immunofluorescence of PRNP (green), SLC39A8 (red), LCN2 (red), ATP6V0A1 (green), SLC3A2 (red), and SLC39A14 (green) in ESCC samples and normal tissues.
Figure 5
Figure 5
Total CNV (A), distribution of CNVs in each chromosome (B), TMB (C), and most common mutations of genes (D) and pathways (E) in the low and high score group based on the TCGA database.
Figure 6
Figure 6
The abundance of 22 immune cell subpopulations in the low and high score group based on the TCGA database.
Figure 7
Figure 7
Anti-cancer drugs with higher sensitivity in the low score group based on the GDSC database (A) and potential inhibitors targeting the ESCC prognostic signature based on the CMap database (B).
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