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Abstract：
The mechanism of copper-induced cellular death was newly discovered and termed cuproptosis. 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.
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. 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.
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.
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. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.
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. 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.
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.
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. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.
摘要：
未经证实：铜诱导的细胞死亡机制是新发现的，称为角化凋亡。在癌细胞中诱导角化凋亡因其在治疗肿瘤疾病中的治愈潜力而备受期待。然而,铁氧还蛋白1（FDX1），角化的核心调节基因，很少被研究，FDX1在肿瘤生物学中的调控仍不清楚。需要对FDX1进行全面的泛癌症分析。
UNASSIGNED：在癌症基因组图谱（TCGA）和基因型-组织表达（GTEx）数据集中，包括了33种类型的肿瘤与配对的正常组织。转录之间的相互作用，蛋白质，磷酸化,和启动子甲基化水平进行了分析。生存,免疫浸润，单细胞FDX1表达，FDX1相关肿瘤突变负荷（TMB），微卫星不稳定性（MSI），stemness,肿瘤免疫功能障碍和排斥（TIDE），和免疫治疗相关分析.通过肾肾透明细胞癌（KIRC）组织微阵列免疫组织化学评估FDX1蛋白的表达。通过体外786-O细胞系的实验进一步探讨了FDX1在KIRC中的功能。
UNASSIGNED：FDX1在15种肿瘤类型中高表达，在11种肿瘤类型中低表达。蛋白质表达的相应变化，磷酸化,已经在几种肿瘤中描述了FDX1的启动子甲基化水平。生存分析显示，FDX1与8个肿瘤的总体生存率和9个肿瘤的无进展生存率有关。免疫浸润和单细胞分析表明FDX1表达在巨噬细胞和单核细胞中不可或缺的作用。多个已建立的免疫治疗队列表明，FDX1可能是肿瘤患者治疗效果的潜在预测指标。组织微阵列分析显示KIRC患者肿瘤组织中FDX1表达降低。FDX1的敲除导致肾肾透明肿瘤细胞中角化的下调。机械上,KIRC中与FDX1相关的基因表达特征与参与三羧酸（TCA）循环的基因富集有关，NOTCH通路,等。几个NOTCH通路基因在KIRC的高和低FDX1组中差异表达。
UNASSIGNED：我们的分析表明，角化的中枢调节基因，FDX1，在各种肿瘤中具有差异表达和修饰水平，这与细胞功能有关，免疫调节，和疾病预后。因此，FDX1依赖性角化可能成为未来治疗肿瘤的新靶点。
UNASSIGNED：在癌症基因组图谱（TCGA）和基因型-组织表达（GTEx）数据集中，包括了33种类型的肿瘤与配对的正常组织。转录之间的相互作用，蛋白质，磷酸化,和启动子甲基化水平进行了分析。生存,免疫浸润，单细胞FDX1表达，FDX1相关肿瘤突变负荷（TMB），微卫星不稳定性（MSI），stemness,肿瘤免疫功能障碍和排斥（TIDE），和免疫治疗相关分析.通过肾肾透明细胞癌（KIRC）组织微阵列免疫组织化学评估FDX1蛋白的表达。通过体外786-O细胞系的实验进一步探讨了FDX1在KIRC中的功能。
UNASSIGNED：FDX1在15种肿瘤类型中高表达，在11种肿瘤类型中低表达。蛋白质表达的相应变化，磷酸化,已经在几种肿瘤中描述了FDX1的启动子甲基化水平。生存分析显示，FDX1与8个肿瘤的总体生存率和9个肿瘤的无进展生存率有关。免疫浸润和单细胞分析表明FDX1表达在巨噬细胞和单核细胞中不可或缺的作用。多个已建立的免疫治疗队列表明，FDX1可能是肿瘤患者治疗效果的潜在预测指标。组织微阵列分析显示KIRC患者肿瘤组织中FDX1表达降低。FDX1的敲除导致肾肾透明肿瘤细胞中角化的下调。机械上,KIRC中与FDX1相关的基因表达特征与参与三羧酸（TCA）循环的基因富集有关，NOTCH通路,等。几个NOTCH通路基因在KIRC的高和低FDX1组中差异表达。
UNASSIGNED：我们的分析表明，角化的中枢调节基因，FDX1，在各种肿瘤中具有差异表达和修饰水平，这与细胞功能有关，免疫调节，和疾病预后。因此，FDX1依赖性角化可能成为未来治疗肿瘤的新靶点。
