Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma
BackgroundThe 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 studi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.981764/full |
| _version_ | 1828089950811193344 |
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| author | Jiahao Xu Zhengang Hu Hui Cao Hao Zhang Peng Luo Jian Zhang Xiaoyan Wang Quan Cheng Quan Cheng Jingbo Li |
| author_facet | Jiahao Xu Zhengang Hu Hui Cao Hao Zhang Peng Luo Jian Zhang Xiaoyan Wang Quan Cheng Quan Cheng Jingbo Li |
| author_sort | Jiahao Xu |
| collection | DOAJ |
| description | BackgroundThe 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.MethodsThirty-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.ResultsFDX1 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.ConclusionOur 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. |
| first_indexed | 2024-04-11T05:49:34Z |
| format | Article |
| id | doaj.art-091b538c52324c549a7b268c7ff9b5d0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T05:49:34Z |
| publishDate | 2022-12-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-091b538c52324c549a7b268c7ff9b5d02022-12-22T04:42:06ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-12-011310.3389/fimmu.2022.981764981764Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinomaJiahao Xu0Zhengang Hu1Hui Cao2Hao Zhang3Peng Luo4Jian Zhang5Xiaoyan Wang6Quan Cheng7Quan Cheng8Jingbo Li9Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Neurosurgery, Xiangya Hospital, Central South University, Changsha, ChinaBrain Hospital of Hunan Province, The Second People's Hospital of Hunan Province, Changsha, ChinaDepartment of Neurosurgery, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Neurosurgery, Xiangya Hospital, Central South University, Changsha, ChinaNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, ChinaDepartment of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, ChinaBackgroundThe 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.MethodsThirty-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.ResultsFDX1 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.ConclusionOur 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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.981764/fullcuproptosisFDX1pan-cancerimmunologyKIRCnotch |
| spellingShingle | Jiahao Xu Zhengang Hu Hui Cao Hao Zhang Peng Luo Jian Zhang Xiaoyan Wang Quan Cheng Quan Cheng Jingbo Li Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma Frontiers in Immunology cuproptosis FDX1 pan-cancer immunology KIRC notch |
| title | Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma |
| title_full | Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma |
| title_fullStr | Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma |
| title_full_unstemmed | Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma |
| title_short | Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma |
| title_sort | multi omics pan cancer study of cuproptosis core gene fdx1 and its role in kidney renal clear cell carcinoma |
| topic | cuproptosis FDX1 pan-cancer immunology KIRC notch |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.981764/full |
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