Cargando…

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

BACKGROUND: 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 stu...

Descripción completa

Detalles Bibliográficos
Autores principales: Xu, Jiahao, Hu, Zhengang, Cao, Hui, Zhang, Hao, Luo, Peng, Zhang, Jian, Wang, Xiaoyan, Cheng, Quan, Li, Jingbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810262/
https://www.ncbi.nlm.nih.gov/pubmed/36605188
http://dx.doi.org/10.3389/fimmu.2022.981764
_version_ 1784863275332141056
author Xu, Jiahao
Hu, Zhengang
Cao, Hui
Zhang, Hao
Luo, Peng
Zhang, Jian
Wang, Xiaoyan
Cheng, Quan
Li, Jingbo
author_facet Xu, Jiahao
Hu, Zhengang
Cao, Hui
Zhang, Hao
Luo, Peng
Zhang, Jian
Wang, Xiaoyan
Cheng, Quan
Li, Jingbo
author_sort Xu, Jiahao
collection PubMed
description BACKGROUND: 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. 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. 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. 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. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.
format Online
Article
Text
id pubmed-9810262
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-98102622023-01-04 Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma Xu, Jiahao Hu, Zhengang Cao, Hui Zhang, Hao Luo, Peng Zhang, Jian Wang, Xiaoyan Cheng, Quan Li, Jingbo Front Immunol Immunology BACKGROUND: 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. 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. 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. 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. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors. Frontiers Media S.A. 2022-12-20 /pmc/articles/PMC9810262/ /pubmed/36605188 http://dx.doi.org/10.3389/fimmu.2022.981764 Text en Copyright © 2022 Xu, Hu, Cao, Zhang, Luo, Zhang, Wang, Cheng and Li https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Xu, Jiahao
Hu, Zhengang
Cao, Hui
Zhang, Hao
Luo, Peng
Zhang, Jian
Wang, Xiaoyan
Cheng, Quan
Li, Jingbo
Multi-omics pan-cancer study of cuproptosis core gene FDX1 and its role in kidney renal clear cell carcinoma
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 Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810262/
https://www.ncbi.nlm.nih.gov/pubmed/36605188
http://dx.doi.org/10.3389/fimmu.2022.981764
work_keys_str_mv AT xujiahao multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma
AT huzhengang multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma
AT caohui multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma
AT zhanghao multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma
AT luopeng multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma
AT zhangjian multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma
AT wangxiaoyan multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma
AT chengquan multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma
AT lijingbo multiomicspancancerstudyofcuproptosiscoregenefdx1anditsroleinkidneyrenalclearcellcarcinoma