Research article

Development and validation of two redox-related genes associated with prognosis and immune microenvironment in endometrial carcinoma


  • Received: 09 December 2022 Revised: 16 February 2023 Accepted: 28 February 2023 Published: 31 March 2023
  • In recent studies, the tumourigenesis and development of endometrial carcinoma (EC) have been correlated significantly with redox. We aimed to develop and validate a redox-related prognostic model of patients with EC to predict the prognosis and the efficacy of immunotherapy. We downloaded gene expression profiles and clinical information of patients with EC from the Cancer Genome Atlas (TCGA) and the Gene Ontology (GO) dataset. We identified two key differentially expressed redox genes (CYBA and SMPD3) by univariate Cox regression and utilised them to calculate the risk score of all samples. Based on the median of risk scores, we composed low-and high-risk groups and performed correlation analysis with immune cell infiltration and immune checkpoints. Finally, we constructed a nomogram of the prognostic model based on clinical factors and the risk score. We verified the predictive performance using receiver operating characteristic (ROC) and calibration curves. CYBA and SMPD3 were significantly related to the prognosis of patients with EC and used to construct a risk model. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low-and high-risk groups. The nomogram developed with clinical indicators and the risk scores was effective in predicting the prognosis of patients with EC. In this study, a prognostic model constructed based on two redox-related genes (CYBA and SMPD3) were proved to be independent prognostic factors of EC and associated with tumour immune microenvironment. The redox signature genes have the potential to predict the prognosis and the immunotherapy efficacy of patients with EC.

    Citation: Yan He, Nannan Cao, Yanan Tian, Xuelin Wang, Qiaohong Xiao, Xiaojuan Tang, Jiaolong Huang, Tingting Zhu, Chunhui Hu, Ying Zhang, Jie Deng, Han Yu, Peng Duan. Development and validation of two redox-related genes associated with prognosis and immune microenvironment in endometrial carcinoma[J]. Mathematical Biosciences and Engineering, 2023, 20(6): 10339-10357. doi: 10.3934/mbe.2023453

    Related Papers:

  • In recent studies, the tumourigenesis and development of endometrial carcinoma (EC) have been correlated significantly with redox. We aimed to develop and validate a redox-related prognostic model of patients with EC to predict the prognosis and the efficacy of immunotherapy. We downloaded gene expression profiles and clinical information of patients with EC from the Cancer Genome Atlas (TCGA) and the Gene Ontology (GO) dataset. We identified two key differentially expressed redox genes (CYBA and SMPD3) by univariate Cox regression and utilised them to calculate the risk score of all samples. Based on the median of risk scores, we composed low-and high-risk groups and performed correlation analysis with immune cell infiltration and immune checkpoints. Finally, we constructed a nomogram of the prognostic model based on clinical factors and the risk score. We verified the predictive performance using receiver operating characteristic (ROC) and calibration curves. CYBA and SMPD3 were significantly related to the prognosis of patients with EC and used to construct a risk model. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low-and high-risk groups. The nomogram developed with clinical indicators and the risk scores was effective in predicting the prognosis of patients with EC. In this study, a prognostic model constructed based on two redox-related genes (CYBA and SMPD3) were proved to be independent prognostic factors of EC and associated with tumour immune microenvironment. The redox signature genes have the potential to predict the prognosis and the immunotherapy efficacy of patients with EC.



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    [1] W. Chen, R. Zheng, P. D. Baade, S. Zhang, H. Zeng, F. Bray, et al., Cancer statistics in China, 2015, CA: Cancer J. Clin., 66 (2016), 115–132. https://doi.org/10.3322/caac.21338
    [2] R. L. Siegel, K. D. Miller, H. E. Fuchs, A. Jemal, Cancer statistics, 2022, CA: Cancer J. Clin., 71 (2021), 7–33. https://doi.org/10.3322/caac.21708 doi: 10.3322/caac.21708
    [3] M. E. Urick, D. W. Bell, Clinical actionability of molecular targets in endometrial cancer, Nat. Rev. Cancer, 19 (2019), 510–521. https://doi.org/10.1038/s41568-019-0177-x doi: 10.1038/s41568-019-0177-x
    [4] L. Mutlu, J. Harold, J. Tymon-Rosario, A. D. Santin, Immune checkpoint inhibitors for recurrent endometrial cancer, Expert Rev. Anticancer Ther., 22 (2022), 249–258. https://doi.org/10.1080/14737140.2022.2044311 doi: 10.1080/14737140.2022.2044311
    [5] J. Ventriglia, I. Paciolla, C. Pisano, S. C. Cecere, M. Di Napoli, R. Tambaro, et al., Immunotherapy in ovarian, endometrial and cervical cancer: State of the art and future perspectives, Cancer Treat. Rev., 59 (2017), 109–116. https://doi.org/10.1016/j.ctrv.2017.07.008 doi: 10.1016/j.ctrv.2017.07.008
    [6] D. Xian, J. Song, L. Yang, X. Xiong, R. Lai, J. Zhong, Emerging roles of redox-mediated angiogenesis and oxidative stress in dermatoses, Oxid. Med. Cell. Longevity, 2019 (2019), 2304018. https://doi.org/10.1155/2019/2304018 doi: 10.1155/2019/2304018
    [7] H. Lan, Y. Gao, Z. Zhao, Z. Mei, F. Wang, Ferroptosis: Redox imbalance and hematological tumorigenesis, Front. Oncol., 12 (2022), 834681. https://doi.org/10.3389/fonc.2022.834681 doi: 10.3389/fonc.2022.834681
    [8] R. Camarda, A. Y. Zhou, R. A. Kohnz, S. Balakrishnan, C. Mahieu, B. Anderton, et al., Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer, Nat. Med., 22 (2016), 427–432. https://doi.org/10.1038/nm.4055 doi: 10.1038/nm.4055
    [9] T. Poplawski, D. Pytel, J. Dziadek, I. Majsterek, Interplay between redox signaling, oxidative stress, and unfolded protein response (UPR) in pathogenesis of human diseases, Oxid. Med. Cell. Longevity, 2019 (2019), 6949347. https://doi.org/10.1155/2019/6949347 doi: 10.1155/2019/6949347
    [10] S. E. Eriksson, S. Ceder, V. J. N. Bykov, K. G. Wiman, p53 as a hub in cellular redox regulation and therapeutic target in cancer, J. Mol. Cell Biol., 11 (2019), 330–341. https://doi.org/10.1093/jmcb/mjz005 doi: 10.1093/jmcb/mjz005
    [11] S. K. Joseph, D. M. Booth, M. P. Young, G. Hajnóczky, Redox regulation of ER and mitochondrial Ca2+ signaling in cell survival and death, Cell Calcium, 79 (2019), 89–97. https://doi.org/10.1016/j.ceca.2019.02.006 doi: 10.1016/j.ceca.2019.02.006
    [12] E. Balta, J. Kramer, Y. Samstag, Redox regulation of the actin cytoskeleton in cell migration and adhesion: on the way to a spatiotemporal view, Front. Cell Dev. Biol., 8 (2020), 618261. https://doi.org/10.3389/fcell.2020.618261 doi: 10.3389/fcell.2020.618261
    [13] J. Pravda, Systemic lupus erythematosus: Pathogenesis at the functional limit of redox homeostasis, Oxid. Med. Cell. Longevity, 2019 (2019), 1651724. https://doi.org/10.1155/2019/1651724 doi: 10.1155/2019/1651724
    [14] K. Mattes, E. Vellenga, H. Schepers, Differential redox-regulation and mitochondrial dynamics in normal and leukemic hematopoietic stem cells: A potential window for leukemia therapy, Crit. Rev. Oncol. Hematol., 144 (2019), 102814. https://doi.org/10.1016/j.critrevonc.2019.102814 doi: 10.1016/j.critrevonc.2019.102814
    [15] A. Cruz-Gregorio, A. K. Aranda-Rivera, J. Pedraza-Chaverri, J. D. Solano, M. E. Ibarra-Rubio, Redox-sensitive signaling pathways in renal cell carcinoma, BioFactors, 48 (2022), 342–358. https://doi.org/10.1002/biof.1784 doi: 10.1002/biof.1784
    [16] Q. Xia, X. Yang, J. L. Lu, C. Q. Liu, J. X. Sun, C. Li, et al., Development and validation of a nine-redox-related long noncoding RNA signature in renal clear cell carcinoma, Oxid. Med. Cell. Longevity, 2020 (2020), 6634247. https://doi.org/10.1155/2020/6634247 doi: 10.1155/2020/6634247
    [17] J. Ren, A. Wang, J. Liu, Q. Yuan, Identification and validation of a novel redox-related lncRNA prognostic signature in lung adenocarcinoma, Bioengineered, 12 (2021), 4331–4348. https://doi.org/10.1080/21655979.2021.1951522 doi: 10.1080/21655979.2021.1951522
    [18] K. Tu, J. Li, H. Mo, Y. Xian, Q. Xu, X. Xiao, Identification and validation of redox-immune based prognostic signature for hepatocellular carcinoma, Int. J. Med. Sci., 18 (2021), 2030–2041. https://doi.org/10.7150/ijms.56289 doi: 10.7150/ijms.56289
    [19] Y. Wu, X. Wei, H. Feng, B. Hu, B. Liu, Y. Luan, et al., Integrated analysis to identify a redox-related prognostic signature for clear cell renal cell carcinoma, Oxid. Med. Cell. Longevity, 2021 (2021), 6648093. https://doi.org/10.1155/2021/6648093 doi: 10.1155/2021/6648093
    [20] Y. Y. Zhang, Z. J. Ni, E. Elam, F. Zhang, K. Thakur, S. Wang, et al., Juglone, a novel activator of ferroptosis, induces cell death in endometrial carcinoma Ishikawa cells, Food Funct., 12 (2021), 4947–4959. https://doi.org/10.1039/D1FO00790D doi: 10.1039/D1FO00790D
    [21] S. Hä nzelmann, R. Castelo, J. Guinney, GSVA: gene set variation analysis for microarray and RNA-seq data, BMC Bioinf., 14 (2013), 7. https://doi.org/10.1186/1471-2105-14-7 doi: 10.1186/1471-2105-14-7
    [22] D. Aran, Z. Hu, A. J. Butte, xCell: digitally portraying the tissue cellular heterogeneity landscape, Genome Biol., 18 (2017), 220. https://doi.org/10.1186/s13059-017-1349-1 doi: 10.1186/s13059-017-1349-1
    [23] H. Sung, J. Ferlay, R. L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA: Cancer J. Clin., 71 (2021), 209–249. https://doi.org/10.3322/caac.21660 doi: 10.3322/caac.21660
    [24] Y. Cai, B. Wang, W. Xu, K. Liu, Y. Gao, C. Guo, et al., Endometrial cancer: Genetic, metabolic characteristics, therapeutic strategies and nanomedicine, Curr. Med. Chem., 28 (2021), 8755–8781. https://doi.org/10.2174/0929867328666210705144456 doi: 10.2174/0929867328666210705144456
    [25] P. A. Ott, Y. J. Bang, D. Berton-Rigaud, E. Elez, M. J. Pishvaian, H. S. Rugo, et al., Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: Results from the KEYNOTE-028 study, J. Clin. Oncol., 35 (2017), 2535–2541. https://doi.org/10.1200/JCO.2017.72.5952 doi: 10.1200/JCO.2017.72.5952
    [26] S. B. Crist, T. Nemkov, R. F. Dumpit, J. Dai, S. J. Tapscott, L. D. True, et al., Unchecked oxidative stress in skeletal muscle prevents outgrowth of disseminated tumour cells, Nat. Cell Biol., 24 (2022), 538–553. https://doi.org/10.1038/s41556-022-00881-4 doi: 10.1038/s41556-022-00881-4
    [27] B. Jiang, J. Zhang, G. Zhao, M. Liu, J. Hu, F. Lin, et al., Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis, Mol. Cell, 82 (2022), 1821–1835.e6. https://doi.org/10.1016/j.molcel.2022.03.016 doi: 10.1016/j.molcel.2022.03.016
    [28] D. G. Franchina, H. Kurniawan, M. Grusdat, C. Binsfeld, L. Guerra, L. Bonetti, et al., Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells, Nat. Commun., 13 (2022), 1789. https://doi.org/10.1038/s41467-022-29426-x doi: 10.1038/s41467-022-29426-x
    [29] D. W. Killilea, A. N. Killilea, Mineral requirements for mitochondrial function: A connection to redox balance and cellular differentiation, Free Radical Biol. Med., 182 (2022), 182–191. https://doi.org/10.1016/j.freeradbiomed.2022.02.022 doi: 10.1016/j.freeradbiomed.2022.02.022
    [30] H. Shyam, N. Singh, S. Kaushik, R. Sharma, A. K. Balapure, Centchroman induces redox-dependent apoptosis and cell-cycle arrest in human endometrial cancer cells, Apoptosis, 22 (2017), 570–584. https://doi.org/10.1007/s10495-017-1346-6 doi: 10.1007/s10495-017-1346-6
    [31] F. Heidari, S. Rabizadeh, M. A. Mansournia, H. Mirmiranpoor, S. S. Salehi, S. Akhavan, et al., Inflammatory, oxidative stress and anti-oxidative markers in patients with endometrial carcinoma and diabetes, Cytokine, 120 (2019), 186–190. https://doi.org/10.1016/j.cyto.2019.05.007 doi: 10.1016/j.cyto.2019.05.007
    [32] Q. Chen, X. Zhong, X. Li, J. Wang, Research advances on the pathogenesis of endometrial serous carcinoma, Chin. J. Obstet. Gynecol., 2 (2020), 142–144. https://doi.org/10.3760/cma.j.issn.0529-567X.2020.02.017 doi: 10.3760/cma.j.issn.0529-567X.2020.02.017
    [33] M. C. Ochoa, C. Razquin, G. Zalba, M. A. Martínez-González, J. A. Martínez, A. Marti, G allele of the -930A > G polymorphism of the CYBA gene is associated with insulin resistance in obese subjects, J. Physiol. Biochem., 64 (2008), 127–133. https://doi.org/10.1007/bf03168240 doi: 10.1007/bf03168240
    [34] A. H. Janneh, B. Ogretmen, Targeting sphingolipid metabolism as a therapeutic strategy in cancer treatment, Cancers, 14 (2022), 2183. https://doi.org/10.3390/cancers14092183 doi: 10.3390/cancers14092183
    [35] E. Tarazona-Santos, M. Machado, W. C. Magalhães, R. Chen, F. Lyon, L. Burdett, et al., Evolutionary dynamics of the human NADPH oxidase genes CYBB, CYBA, NCF2, and NCF4: functional implications, Mol. Biol. Evol., 30 (2013), 2157–2167. https://doi.org/10.1093/molbev/mst119 doi: 10.1093/molbev/mst119
    [36] L. Zhu, B. Miao, D. Dymerska, M. Kuswik, E. Bueno-Martínez, L. Sanoguera-Miralles, et al., Germline variants of CYBA and TRPM4 predispose to familial colorectal cancer, Cancers, 14 (2022), 670. https://doi.org/10.3390/cancers14030670 doi: 10.3390/cancers14030670
    [37] R. Paolillo, M. Boulanger, P. Gâtel, L. Gabellier, M. De Toledo, D. Tempé, et al., The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of acute myeloid leukemias, Haematologica, 107 (2022). https://doi.org/10.3324/haematol.2021.279889 doi: 10.3324/haematol.2021.279889
    [38] M. Rose, T. Cardon, S. Aboulouard, N. Hajjaji, F. Kobeissy, M. Duhamel, et al., Surfaceome proteomic of glioblastoma revealed potential targets for immunotherapy, Front. Immunol., 12 (2021), 746168. https://doi.org/10.3389/fimmu.2021.746168 doi: 10.3389/fimmu.2021.746168
    [39] J. Wang, J. Li, J. Gu, J. Yu, S. Guo, Y. Zhu, et al., Abnormal methylation status of FBXW10 and SMPD3, and associations with clinical characteristics in clear cell renal cell carcinoma, Oncol. Lett., 10 (2015), 3073–3080. https://doi.org/10.3892/ol.2015.3707 doi: 10.3892/ol.2015.3707
    [40] A. Montfort, F. Bertrand, J. Rochotte, J. Gilhodes, T. Filleron, J. Milhès, et al., Neutral sphingomyelinase 2 heightens anti-melanoma immune responses and Anti-PD-1 therapy efficacy, Cancer Immunol. Res., 9 (2021), 568–582. https://doi.org/10.1158/2326-6066.CIR-20-0342 doi: 10.1158/2326-6066.CIR-20-0342
    [41] K. Revill, T. Wang, A. Lachenmayer, K. Kojima, A. Harrington, J. Li, et al., Genome-wide methylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular carcinoma, Gastroenterology, 145 (2013), 1424–1435. https://doi.org/10.1053/j.gastro.2013.08.055 doi: 10.1053/j.gastro.2013.08.055
    [42] X. Liu, J. Wu, D. Zhang, Z. Bing, J. Tian, M. Ni, et al., Identification of potential key genes associated with the pathogenesis and prognosis of gastric cancer based on integrated bioinformatics analysis, Front. Genet., 9 (2018), 265. https://doi.org/10.3389/fgene.2018.00265 doi: 10.3389/fgene.2018.00265
    [43] Y. H. Lee, C. W. Tan, A. Venkatratnam, C. S. Tan, L. Cui, S. F. Loh, et al., Dysregulated sphingolipid metabolism in endometriosis, J. Clin. Endocrinol. Metab., 99 (2014), E1913–1921. https://doi.org/10.1210/jc.2014-1340 doi: 10.1210/jc.2014-1340
    [44] C. Zhang, Z. Li, F. Qi, X. Hu, J. Luo, Exploration of the relationships between tumor mutation burden with immune infiltrates in clear cell renal cell carcinoma, Ann. Transl. Med., 7 (2019), 648. https://doi.org/10.21037/atm.2019.10.84 doi: 10.21037/atm.2019.10.84
    [45] J. Lu, P. Wilfred, D. Korbie, M. Trau, Regulation of canonical oncogenic signaling pathways in cancer via DNA methylation, Cancers, 12 (2020), 3199. https://doi.org/10.3390/cancers12113199 doi: 10.3390/cancers12113199
    [46] Y. Shen, M. Takahashi, H. M. Byun, A. Link, N. Sharma, F. Balaguer, et al., Boswellic acid induces epigenetic alterations by modulating DNA methylation in colorectal cancer cells, Cancer Biol. Ther., 13 (2012), 542–552. https://doi.org/10.4161/cbt.19604 doi: 10.4161/cbt.19604
    [47] K. Revill, T. Wang, A. Lachenmayer, K. Kojima, A. Harrington, J. Li, et al., Genome-wide methylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular carcinoma, Gastroenterology, 145 (2013), 1424–1435.e25. https://doi.org/10.1053/j.gastro.2013.08.055 doi: 10.1053/j.gastro.2013.08.055
    [48] Q. Song, X. Zhu, L. Jin, M. Chen, W. Zhang, J. Su, SMGR: a joint statistical method for integrative analysis of single-cell multi-omics data, NAR Genomics Bioinf., 4 (2022), lqac056. https://doi.org/10.1093/nargab/lqac056 doi: 10.1093/nargab/lqac056
    [49] Z. Tang, T. Zhang, B. Yang, J. Su, Q. Song, spaCI: deciphering spatial cellular communications through adaptive graph model, Briefings Bioinf., 24 (2023), bbac563.50. https://doi.org/10.1093/bib/bbac563 doi: 10.1093/bib/bbac563
    [50] M. Zheng, Y. Hu, R. Gou, S. Li, X. Nie, X. Li, et al., Development of a seven-gene tumor immune microenvironment prognostic signature for high-risk grade III endometrial cancer, Mol. Ther. Oncolytics, 22 (2021), 294–306. https://doi.org/10.1016/j.omto.2021.07.002 doi: 10.1016/j.omto.2021.07.002
    [51] Y. Fan, X. Li, L. Tian, J. Wang, Identification of a metabolism-related signature for the prediction of survival in endometrial cancer patients, Front. Oncol., 11 (2021), 630905. https://doi.org/10.3389/fonc.2021.630905 doi: 10.3389/fonc.2021.630905
    [52] S. Singh, X. H. F. Zhang, J. M. Rosen, TIME is a great healer-targeting myeloid cells in the tumor immune microenvironment to improve triple-negative breast cancer outcomes, Cells, 10 (2020), 11. https://doi.org/10.3390/cells10010011 doi: 10.3390/cells10010011
    [53] I. Mito, H. Takahashi, R. Kawabata-Iwakawa, S. Ida, H. Tada, K. Chikamatsu, Comprehensive analysis of immune cell enrichment in the tumor microenvironment of head and neck squamous cell carcinoma, Sci. Rep., 11 (2021), 16134. https://doi.org/10.1038/s41598-021-95718-9 doi: 10.1038/s41598-021-95718-9
    [54] Z. Abdulrahman, S. J. Santegoets, G. Sturm, P. Charoentong, M. E. Ijsselsteijn, A. Somarakis, et al., Tumor-specific T cells support chemokine-driven spatial organization of intratumoral immune microaggregates needed for long survival, J. ImmunoTher. Cancer, 10 (2022), e004346. http://dx.doi.org/10.1136/jitc-2021-004346 doi: 10.1136/jitc-2021-004346
    [55] C. F. Friedman, J. D. Hainsworth, R. Kurzrock, D. R. Spigel, H. A. Burris, C. J. Sweeney, et al., Atezolizumab treatment of tumors with high tumor mutational burden from mypathway, a multicenter, open-label, phase IIa multiple basket study, Cancer Discov., 12 (2022), 654–669. https://doi.org/10.1158/2159-8290.CD-21-0450 doi: 10.1158/2159-8290.CD-21-0450
    [56] M. J. Riggs, N. Lin, C. Wang, D. W. Piecoro, R. W. Miller, O. A. Hampton, et al., DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden, PLoS One, 15 (2020), e0244558. https://doi.org/10.1371/journal.pone.0244558 doi: 10.1371/journal.pone.0244558
    [57] Y. Zhang, J. Zhang, Z. Shao, L. Zhao, Y. Zhang, S. Zhang, et al., Mutational landscapes and tumour mutational burden expression in endometrial cancer, Ann. Onco., 30 (2019), v424–v425. https://doi.org/10.1093/annonc/mdz250.048 doi: 10.1093/annonc/mdz250.048
    [58] M. Collin, Immune checkpoint inhibitors: a patent review (2010–2015), Expert Opin. Ther. Pat., 26 (2016), 555–564. https://doi.org/10.1080/13543776.2016.1176150 doi: 10.1080/13543776.2016.1176150
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