FDX1 is a Potential Prognostic Biomarker Related to Cuproptosis and Immune Infiltration for Patients with Kidney Clear Cell Carcinoma
DOI:
https://doi.org/10.21649/akemu.v30i4.5531Keywords:
Mitochondrial enzyme ferredoxin 1, Cuproptosis, Kidney clear cell carcinoma, Prognostic, Immune infiltratesAbstract
Background: Currently, the mechanisms of copper-induced cell death have attracted the attention of scientists. Since Cu homeostasis has a significant effect on angiogenesis response and immune function, cuproptosis is proposed as a new concept. FDX is a Cuproptosis-related gene because its dysfunction can suppress lipoic acid synthesis and regulate Cu-induced cell death.
Objective: To examine the association between the expression level of FDX1 and clinical characteristics, survival, and immune infiltration for kidney clear cell carcinoma patients.
Method: TCGA database followed the ethical policies of human subject protection. The sampling technique of TCGA was that samples were supposed to contain at least 80% tumor tissue and 20% necrotic normal tissue. Nucleic acids were extracted and genotype was determined to obtain genomic data. The data of 613 American patients from TCGA database was collected for this bioinformatics study based on the diagnostic criteria of KIRC. The study design consisted of Pan-cancer analysis, the Cox regression, the Kaplan-Meier model, Kyoto Encyclopedia of Genes and Genome analyses, Gene Ontology to analyze the progression and survival, immune infiltrate levels, and enrichment effect.
Results: The FDX1 level was significantly lower in KIRC analyzed by Wilcoxon test. In Pearson correlation analyses, the expression level of FDX1 was significantly positive related to the overall survival, while it was negatively associated with the immune infiltrate. The FDX1 expression levels and the infiltration level of T CD8+ cells, T regulatory cells, B memory cells, and NK cells had negative correlations, while it was negatively associated with the enrichment effects on inflammation and immune functions and signaling pathways.
Conclusion: FDX1 is a potential Cuproptosis-related prognostic indicator for the immunotherapy of KIRC, while correlations do not prove causations
References
Gropper SS, Smith JL, Carr TP. Essential trace and ultratrace minerals. Advanced nutrition and human metabolism. 2012;6(1):484-5.
Shanbhag VC, Gudekar N, Jasmer K, Papageorgiou C, Singh K, Petris MJ. Copper metabolism as a unique vulnerability in cancer. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2021;1868(2):118893.
Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 2022;375(6586):1254-1261.
Tsvetkov P, Detappe A, Cai K, Keys HR, Brune Z, Ying W, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol 2019;15(7): 681-689.
Cai K, Tonelli M, Frederick RO, Markley JL. Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron-Sulfur Cluster Biosynthesis. Biochemistry 2017;56(3):487-499.
Sheftel AD, Stehling O, Pierik AJ, Elsässer H-P, Mühlenhoff U, Webert H, et al. Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis. Proc Natl Acad Sci U S A. 2010;107(26):11775-11780.
Shi Y, Ghosh M, Kovtunovych G, Crooks DR, Rouault TA. Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis. Biochim Biophys Acta Mol Cell Res 2012;1823(2):484-492.
Sun S, Mao W, Wan L, Pan K, Deng L, Zhang L, et al. Metastatic Immune-Related Genes for Affecting Prognosis and Immune Response in Renal Clear Cell Carcinoma. Front Mol Biosci 2022;8(1):794326.
Mittrücker HW, Visekruna A, Huber M. Heterogeneity in the differentiation and function of CD8⁺ T cells. Arch Immunol Ther Exp (Warsz) 2014;62(6):449-458.
Seifert M, Küppers R. Human memory B cells. Leukemia 2016;30(12):2283-2292.
Jiang Y, Wang C, Zhou S. Targeting tumor microenvironment in ovarian cancer: Premise and promise. Biochim Biophys Acta Rev Cancer, 2020;1873(2):188361. doi: 10.1016/j.bbcan.2020.188361.
Zhang Z, Zeng X, Wu Y, Liu Y, Zhang X, Song Z. Cuproptosis-Related Risk Score Predicts Prognosis and Characterizes the Tumor Microenvironment in Hepatocellular Carcinoma. Front Immunol 2022;13(1):925618.
Zhang Z, Ma Y, Guo X, Du Y, Zhu Q, Wang X, et al. FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma. Front Pharmacol 2021;12(1):749134.
Wang L, Cao Y, Guo W, Xu J. High expression of cuproptosis-related gene FDX1 in relation to good prognosis and immune cells infiltration in colon adenocarcinoma (COAD). Journal of Cancer Research and Clinical Oncology. 2023;149(1):15-24.
Zhang C, Zeng Y, Guo X, Shen H, Zhang J, Wang K, et al. Pan-cancer analyses confirmed the cuproptosis-related gene FDX1 as an immunotherapy predictor and prognostic biomarker. Front Genet 2022;13(1):923737.
Sharifi L, Nowroozi MR, Amini E, Arami MK, Ayati M, Mohsenzadegan M. A review on the role of M2 macrophages in bladder cancer; pathophysiology and targeting. International Immunopharmacol 2019;76(1):105880.
Salmaninejad A, Valilou SF, Soltani A, Ahmadi S, Abarghan YJ, Rosengren RJ, et al. Tumor-associated macrophages: role in cancer development and therapeutic implications. Cellular Oncology 2019;42(1):591-608.
Ribatti D, Ranieri G. Tryptase, a novel angiogenic factor stored in mast cell granules. Experimental Cell Research 2015;332(2):157-162.
Bian Z, Fan R, Xie L. A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma. Genes (Basel). 2022;13(5):851.
Corthay A. How do regulatory t cells work? Scandinavian Journal of Immunology 2009;70(4):326–336.
Winerdal ME, Krantz D, Hartana CA, Zirakzadeh AA, Linton L, Bergman EA, et al. Urinary bladder cancer tregs suppress MMP2 and potentially regulate invasiveness. Cancer immunology research. 2018;6(5):528-38.
Kaufmann U, Kahlfuss S, Yang J, Ivanova E, Koralov SB, Feske S. Calcium Signaling Controls Pathogenic Th17 Cell-Mediated Inflammation by Regulating Mitochondrial Function. Cell Metab 2019;29(5):1104-1118.
Oddos S, Dunsby C, Purbhoo MA, Chauveau A, Owen DM, Neil MAA, et al. High-speed high-resolution imaging of intercellular immune synapses using optical tweezers. Biophys J 2008;95(10): 66-68.
Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, et al. The Immunological Synapse: A Molecular Machine Controlling T Cell Activation. Science 1999;285(5425):221-227.
Prager I, Watzl C. Mechanisms of natural killer cell-mediated cellular cytotoxicity. Journal of Leukocyte Biology 2019:105(6):1319-1329.
Clark LB, Foy TM, Noelle RJ. CD40 and its ligand. Adv Immunol 1996:63(1):43-78.
Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduction and Targeted Therapy 2021;6(1):263-309.
Takeda K, Akira S. TLR signaling pathways. Semin Immunol 2004;16(1):3-9.
Morikawa T, Sugiyama A, Kume H, Ota S, Kashima T, Tomita K, et al. Identification of toll-like receptor 3 as a potential therapeutic target in clear cell renal cell carcinoma. Clinical Cancer Research 2007;13(19):5703–5709.
Okazaki T, Honjo T. PD-1 and PD-1 ligands: From discovery to clinical application. International Immunology 2007:19(17):813-824.
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