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. 2022 Dec 20:13:981764.
doi: 10.3389/fimmu.2022.981764. eCollection 2022.

Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma

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Multi-omics pan-cancer study of cuproptosis core gene VSports注册入口 - FDX1 and its role in kidney renal clear cell carcinoma

Jiahao Xu et al. Front Immunol. .

Abstract

Background: The mechanism of copper-induced cellular death was newly discovered and termed cuproptosis VSports手机版. Inducing cuproptosis in cancer cells is well anticipated for its curative potential in treating tumor diseases. However, ferredoxin 1 (FDX1), the core regulatory gene in cuproptosis, is rarely studied, and the regulation of FDX1 in tumor biology remains obscure. A comprehensive pan-cancer analysis of FDX1 is needed. .

Methods: Thirty-three types of tumors were included with paired normal tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets. The interaction between transcription, protein, phosphorylation, and promoter methylation levels was analyzed. Survival, immune infiltration, single-cell FDX1 expression, FDX1-related tumor mutational burden (TMB), microsatellite instability (MSI), stemness, tumor immune dysfunction and exclusion (TIDE), and immunotherapy-related analyses were performed V体育安卓版. FDX1 protein expression was assessed by kidney renal clear cell carcinoma (KIRC) tissue microarray immunohistochemistry. The function of FDX1 in KIRC was further explored by experiments in 786-O cell lines in vitro. .

Results: FDX1 is highly expressed in 15 tumor types and lowly expressed in 11 tumor types. The corresponding changes in protein expression, phosphorylation, and promoter methylation level of FDX1 have been described in several tumors. Survival analysis showed that FDX1 was related to favorable or poor overall survival in eight tumors and progression-free survival in nine tumors. Immune infiltration and single-cell analysis indicated the indispensable role of FDX1 expression in macrophages and monocytes. Multiple established immunotherapy cohorts suggested that FDX1 may be a potential predictor of treatment effects for tumor patients. Tissue microarray analysis showed decreased FDX1 expression in KIRC patients' tumor tissues. Knockdown of FDX1 resulted in the downregulation of cuproptosis in kidney renal clear tumor cells. Mechanistically, the FDX1-associated gene expression signature in KIRC is related to the enrichment of genes involved in the tricarboxylic acid (TCA) cycle, NOTCH pathway, etc. Several NOTCH pathway genes were differentially expressed in the high- and low-FDX1 groups in KIRC V体育ios版. .

Conclusion: Our analysis showed that the central regulatory gene of cuproptosis, FDX1, has differential expression and modification levels in various tumors, which is associated with cellular function, immune modulation, and disease prognosis VSports最新版本. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors. .

Keywords: FDX1; KIRC; cuproptosis; immunology; notch; pan-cancer V体育平台登录. .

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest V体育官网入口. The reviewer LS declared a shared affiliation with the authors JX, ZH, HZ, XW, QC at the time of review.

Figures

Figure 1
Figure 1
The mechanism of cuproptosis and expression of FDX1 at different levels. (A) FDX1 works as the core regulatory gene in the process of copper-induced death. (B) FDX1 is differently expressed in the 33 tumors at the transcriptional level. (C, D) Protein level and phosphorylation of FDX1 in different tumors and normal tissues based on data from CTPAC. ns, not significant, p ≥ 0.05; *p < 0.05; **p < 0.01; ***p < 0.001. (Cu, copper; FDX1, ferredoxin 1; TCA, tricarboxylic acid; DLAT, dihydrolipoamide S-acetyltransferase).
Figure 2
Figure 2
Methylation of the FDX1 promoter and correlation between methylation probes and the FDX1 expression. (A) Methylation beta value of the FDX1 promoter in tumors and normal tissues. (B) Correlation between the FDX1 expression and six FDX1 promoter methylation probes. The correlation with the highest r value and p < 0.001 was marked with black boxes. (C–E) The spot correlation plot between the methylation of probes and the FDX1 expression in UCS, PCPG, and ACC. ns, not significant, p ≥ 0.05; *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 3
Figure 3
Survival analysis of FDX1 in tumors and TMB, MSI, and stemness analysis of FDX1. (A) Overall survival in different tumors based on the FDX1 expression 50% cutoff grouping. (B) Progression-free survival in different tumors based on the FDX1 expression 50% cutoff grouping. (C, D) The Kaplan–Meier plot of LGG and KIRC based on the FDX1 expression 50% cutoff grouping. (E–G) Tumor mutant burden (TMB), microsatellite instability (MSI), and stemness analysis of FDX1. ns, not significant, p ≥ 0.05; *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 4
Figure 4
Immune infiltration analysis of FDX1. (A) The correlation heatmap between the six immune cells and FDX1 expression in tumors based on two or three algorithms. (B–G) The correlation plot of those having consistent r values based on the different algorithms. ns, not significant, p ≥ 0.05; *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 5
Figure 5
Single-cell analysis of FDX1 expression. (A) Left: FDX1 expression in different cells. Right: FDX1 expression based on malignancy classification. (B, C) Single-cell profile and FDX1 expression in GBM and KIRC.
Figure 6
Figure 6
Immunotherapy-related analysis of FDX1. (A) Correlation between FDX1 and CD274 (PD-L1) in the TCGA tumor cohorts. The black box means r > 0.3 and p < 0.05. (B) The TIDE scores between the high- and low-FDX1 groups in the tumors. (C) The distribution between immunotherapy progression and FDX1 expression. (D–F) The Kaplan–Meier plot of patients under immunotherapy between the high and low FDX1 expression groups. ns p ≥ 0.05, *p < 0.05, **p< 0.01, ***p < 0.001.
Figure 7
Figure 7
IHC of FDX1 in the kidney renal clear cell carcinoma tissue microarray and in vitro experiments. (A) The pictures of IHC under the microscope. The FDX1-positive areas are tan-colored. (B) Comparison of the FDX1-positive IHC areas between tumor and adjacent normal tissues based on ImageJ quantification. (C) The relative expression of FDX1 in 786-O cells transfected with si-FDX1. (D) The cell growth OD value (450 nm) assessed by CCK-8 kit after 24 h with the addition of elesclomol+Cu2+. A higher OD value means more living cells. The elesclomol+Cu2+ was used to induce cuproptosis. ns means not significant, p ≥ 0.05.
Figure 8
Figure 8
Gene set enrichment analysis (GSEA) of FDX1 in KIRC. (A) Differentially expressed genes based on the FDX1 expression 50% cutoff grouping and the volcano plot. The red spots mean upregulated genes, and the green spots mean downregulated genes. (B) Dot plot of GSEA in 10 cancer types. The red dot means that the gene set is enriched in the high-FDX1 group, while the green dot means that the gene set is enriched in the low-FDX1 group. (C) The GSEA plot of the NOTCH-related gene sets. (D) The expression of the 15 NOTCH pathway genes between high- and low-FDX1 groups (50% cutoff). p ≥ 0.05, *p < 0.05, **p < 0.01, ****p < 0.0001.

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