Biological characteristics and clinical significance of cuproptosis-related genes in lung adenocarcinoma_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

SONG Congkuan , PAN Shize , LI Ning ,  GENG Qing

Department of Thoracic Surgery, Renmin Hospital of Wuhan University (Hubei Provincial People's Hospital), Wuhan, 430000, P. R. China;

Corresponding author：

GENG Qing, Email: gengqingwhu@whu.edu.cn

Keywords：

Cuproptosis; lung adenocarcinoma; biological characteristics

DOI：

10.7507/1007-4848.202204017

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the biological characteristics and clinical significance of cuproptosis-related genes in lung adenocarcinoma (LUAD) based on the multi-omics data from The Cancer Genome Atlas. Methods The cuproptosis-related genes were obtained from a study published in Science in March 2022. The whole genome data were used to reveal the mutation spectrum and copy number variation landscape of cuproptosis-related genes in LUAD and analyze its effects on transcriptome expression. Cuproptosis-related genes were annotated using Metascape analysis to further understand the pathways or functions in which these genes were involved. Subsequent univariate Cox analysis and Kaplan-Meier methods determined the prognosis of these genes in LUAD patients, and CellMiner analysis were used to identify those potential anticancer drugs for potentially targeting cuproptosis-related genes. Results Cuproptosis-related genes were less frequently mutated in LUAD, and the effect of gene mutations on transcriptomic expression may depend on the type of mutation. Gene copy number variation was an important factor resulting in the disordered expression of cuproptosis-related genes. The 16 cuproptosis-related genes were mainly involved in glyoxylate metabolism and glycine degradation, copper ion entry, proteolitidylation, cellular amino acid catabolism process, oxidative stress response, etc. Among them, 6 genes (DLD, FDX1, DLAT, DLST, PDHA1, CDKN2A) were prognostic risk genes in LUAD. The CellMiner analysis suggested that 13 drugs were associated with 7 cuproptosis-related genes and they might be potential anticancer drugs for potentially targeting cuproptosis. Conclusion This study reveals the biological characteristics and clinical significance of cuproptosis-related genes in LUAD, and provides some reference and theoretical basis for the subsequent research of cuproptosis in cancer.

Citation： SONG Congkuan, PAN Shize, LI Ning, GENG Qing. Biological characteristics and clinical significance of cuproptosis-related genes in lung adenocarcinoma. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2023, 30(6): 858-866. doi: 10.7507/1007-4848.202204017 Copy

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14.	Liu L, Cao J, Zhao J, et al. PDHA1 gene knockout in human esophageal squamous cancer cells resulted in greater warburg effect and aggressive features in vitro and in vivo. Onco Targets Ther, 2019, 12: 9899-9913.
15.	Zhong Y, Huang R, Li X, et al. Decreased expression of PDHE1alpha predicts worse clinical outcome in esophageal squamous cell carcinoma. Anticancer Res, 2015, 35(10): 5533-5538.
16.	Zhong Y, Li X, Ji Y, et al. Pyruvate dehydrogenase expression is negatively associated with cell stemness and worse clinical outcome in prostate cancers. Oncotarget, 2017, 8(8): 13344-13356.
17.	Song L, Liu D, Zhang X, et al. Low expression of PDHA1 predicts poor prognosis in gastric cancer. Pathol Res Pract, 2019, 215(3): 478-482.
18.	Liu Z, Yu M, Fei B, et al. miR215p targets PDHA1 to regulate glycolysis and cancer progression in gastric cancer. Oncol Rep, 2018, 40(5): 2955-2963.
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24.	Chen Y, Xu T, Xie F, et al. Evaluating the biological functions of the prognostic genes identified by the Pathology Atlas in bladder cancer. Oncol Rep, 2021, 45(1): 191-201.
25.	Xu G, Yan T, Peng Q, et al. Overexpression of the Lias gene attenuates hepatic steatosis in Leprdb/db mice. J Endocrinol, 2021, 248(2): 119-131.
26.	Baker PN, Friederich MW, Swanson MA, et al. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain, 2014, 137(Pt 2): 366-379.

1. Chen R, Xu X, Qian Z, et al. The biological functions and clinical applications of exosomes in lung cancer. Cell Mol Life Sci, 2019, 76(23): 4613-4633.
2. Wei S, Zhang ZY, Fu SL, et al. Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma. Cell Death Dis, 2017, 8(5): e2829.
3. Song C, Guo Z, Yu D, et al. A prognostic nomogram combining immune-related gene signature and clinical factors predicts survival in patients with lung adenocarcinoma. Front Oncol, 2020, 10: 1300.
4. Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586): 1254-1261.
5. Colaprico A, Silva TC, Olsen C, et al. TCGAbiolinks: An R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res, 2016, 44(8): e71.
6. Reinhold WC, Sunshine M, Liu H, et al. CellMiner: A web-based suite of genomic and pharmacologic tools to explore transcript and drug patterns in the NCI-60 cell line set. Cancer Res, 2012, 72(14): 3499-3511.
7. Luo Z, Liu W, Sun P, et al. Pan-cancer analyses reveal regulation and clinical outcome association of the shelterin complex in cancer. Brief Bioinform, 2021, 22(5): bbaa441.
8. Imamichi Y, Mizutani T, Ju Y, et al. Transcriptional regulation of human ferredoxin 1 in ovarian granulosa cells. Mol Cell Endocrinol, 2013, 370(1-2): 1-10.
9. Shi Y, Ghosh M, Kovtunovych G, et al. Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis. Biochim Biophys Acta, 2012, 1823(2): 484-492.
10. Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol, 2019, 15(7): 681-689.
11. 陈晨, 彭培佩, 王健, 等. 利用NCI-H1975细胞筛选对奥西替尼耐药的铁氧还蛋白1基因及其功能鉴定. 中国药理学与毒理学杂志, 2019, 33(4): 265-272.
12. Kaplon J, Zheng L, Meissl K, et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature, 2013, 498(7452): 109-112.
13. Kim JW, Tchernyshyov I, Semenza GL, et al. HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab, 2006, 3(3): 177-185.
14. Liu L, Cao J, Zhao J, et al. PDHA1 gene knockout in human esophageal squamous cancer cells resulted in greater warburg effect and aggressive features in vitro and in vivo. Onco Targets Ther, 2019, 12: 9899-9913.
15. Zhong Y, Huang R, Li X, et al. Decreased expression of PDHE1alpha predicts worse clinical outcome in esophageal squamous cell carcinoma. Anticancer Res, 2015, 35(10): 5533-5538.
16. Zhong Y, Li X, Ji Y, et al. Pyruvate dehydrogenase expression is negatively associated with cell stemness and worse clinical outcome in prostate cancers. Oncotarget, 2017, 8(8): 13344-13356.
17. Song L, Liu D, Zhang X, et al. Low expression of PDHA1 predicts poor prognosis in gastric cancer. Pathol Res Pract, 2019, 215(3): 478-482.
18. Liu Z, Yu M, Fei B, et al. miR215p targets PDHA1 to regulate glycolysis and cancer progression in gastric cancer. Oncol Rep, 2018, 40(5): 2955-2963.
19. Gu C, Wang F, Zhang YT, et al. Microglial MT1 activation inhibits LPS-induced neuroinflammation via regulation of metabolic reprogramming. Aging Cell, 2021, 20(6): e13375.
20. Chen J, Guccini I, Di Mitri D, et al. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer. Nat Genet, 2018, 50(2): 219-228.
21. Stowe RC, Sun Q, Elsea SH, et al. LIPT1 deficiency presenting as early infantile epileptic encephalopathy, Leigh disease, and secondary pyruvate dehydrogenase complex deficiency. Am J Med Genet A, 2018, 176(5): 1184-1189.
22. Mayr JA, Feichtinger RG, Tort F, et al. Lipoic acid biosynthesis defects. J Inherit Metab Dis, 2014, 37(4): 553-563.
23. Tort F, Ferrer-Cortes X, Ribes A. Differential diagnosis of lipoic acid synthesis defects. J Inherit Metab Dis, 2016, 39(6): 781-793.
24. Chen Y, Xu T, Xie F, et al. Evaluating the biological functions of the prognostic genes identified by the Pathology Atlas in bladder cancer. Oncol Rep, 2021, 45(1): 191-201.
25. Xu G, Yan T, Peng Q, et al. Overexpression of the Lias gene attenuates hepatic steatosis in Leprdb/db mice. J Endocrinol, 2021, 248(2): 119-131.
26. Baker PN, Friederich MW, Swanson MA, et al. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain, 2014, 137(Pt 2): 366-379.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Biological characteristics and clinical significance of cuproptosis-related genes in lung adenocarcinoma

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