{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:54:32Z","timestamp":1753890872749,"version":"3.41.2"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Malignant pleural mesothelioma (MPM) is a malignant tumor originating from pleural mesothelial cells and has a high mortality rate worldwide. With the advent of immunotherapy in MPM treatment, there is an urgent need to elucidate the immune-related mechanisms in this caner.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Single-sample gene set enrichment analysis (ssGSEA) was used to score the immunocytes infiltration of data from different database sources. Identification of immunocyte-related genes was performed with weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs) analysis, and correlation analysis. Pan-caner analysis was performed using \u201cDiffExp\u201d and \u201cCorrelation\u201d modules in TIMER.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> T-helper 2 (Th2) cell was found to be a poor prognostic factor for patients with MPM. Then a transcription factor, NFE2L3, was identified as a biomarker that showed a strong positive correlation with Th2 cell infiltration, and was highly expressed in MPM tissues and was related to the poor prognosis of these patients. At the same time, multiple NFE2L3 methylation sites were negatively correlated with Th2 cell infiltration, and patients with a high degree of methylation enjoy a better prognosis. Pan-caner analysis indicated that NFE2L3 might promote the differentiation of Th2 cells through the IL-2\/STAT5\/NLRP3 signaling pathway in MPM and many other cancers.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> We believe that NFE2L3 can serve as a potential biomarker related to the diagnosis and prognosis of patients with MPM, and speculate that NFE2L3 could promote Th2 cell differentiation <jats:italic>via<\/jats:italic> IL-2\/STAT5\/NLRP3 signaling pathway in MPM and many other cancers.<\/jats:p>","DOI":"10.3389\/fgene.2022.805256","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T07:17:14Z","timestamp":1652858234000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["NFE2L3 as a Novel Biomarker Associated With IL-2\/STAT5\/NLRP3 Signaling Pathway in Malignant Pleural Mesothelioma and Other Cancers"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhen","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/S0140-6736(20)32714-8","article-title":"First-line Nivolumab Plus Ipilimumab in Unresectable Malignant Pleural Mesothelioma (CheckMate 743): a Multicentre, Randomised, Open-Label, Phase 3 Trial","volume":"397","author":"Baas","year":"2021","journal-title":"The Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: Archive for Functional Genomics Data Sets-Update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1037\/a0028087","article-title":"Testing the Significance of a Correlation with Nonnormal Data: Comparison of Pearson, Spearman, Transformation, and Resampling Approaches","volume":"17","author":"Bishara","year":"2012","journal-title":"Psychol. Methods"},{"key":"B4","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/ni.3202","article-title":"The Receptor NLRP3 Is a Transcriptional Regulator of TH2 Differentiation","volume":"16","author":"Bruchard","year":"2015","journal-title":"Nat. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/ng.3520","article-title":"Comprehensive Genomic Analysis of Malignant Pleural Mesothelioma Identifies Recurrent Mutations, Gene Fusions and Splicing Alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1016\/j.celrep.2019.09.087","article-title":"NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor","volume":"29","author":"Bury","year":"2019","journal-title":"Cel Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The Cancer Genome Atlas Pan-Cancer Analysis Project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.lungcan.2013.11.026","article-title":"A Systematic Review and Meta-Analysis of Surgical Treatments for Malignant Pleural Mesothelioma","volume":"83","author":"Cao","year":"2014","journal-title":"Lung Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"402","DOI":"10.3322\/caac.21572","article-title":"Mesothelioma: Scientific Clues for Prevention, Diagnosis, and Therapy","volume":"69","author":"Carbone","year":"2019","journal-title":"CA A. Cancer J. Clin."},{"key":"B10","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cel Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"574","DOI":"10.21037\/tlcr.2018.04.10","article-title":"Current Chemotherapy Strategies in Malignant Pleural Mesothelioma","volume":"7","author":"de Gooijer","year":"2018","journal-title":"Transl. Lung Cancer Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1084\/jem.20101876","article-title":"Intratumor T Helper Type 2 Cell Infiltrate Correlates with Cancer-Associated Fibroblast Thymic Stromal Lymphopoietin Production and Reduced Survival in Pancreatic Cancer","volume":"208","author":"De Monte","year":"2011","journal-title":"J. Exp. Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nature10189","article-title":"Oncogene-induced Nrf2 Transcription Promotes ROS Detoxification and Tumorigenesis","volume":"475","author":"DeNicola","year":"2011","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2162","DOI":"10.1158\/0008-5472.CAN-11-3687","article-title":"T-regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis: Figure 1","volume":"72","author":"Facciabene","year":"2012","journal-title":"Cancer Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s00428-020-02980-9","article-title":"Challenges in Lung and Thoracic Pathology: Molecular Advances in the Classification of Pleural Mesotheliomas","volume":"478","author":"Fernandez-Cuesta","year":"2021","journal-title":"Virchows Arch."},{"key":"B16","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1177\/2515245919847202","article-title":"Evaluating Effect Size in Psychological Research: Sense and Nonsense","volume":"2","author":"Funder","year":"2019","journal-title":"Adv. Methods Practices Psychol. Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1146\/annurev-immunol-101619-031510","article-title":"30 Years of Biotherapeutics Development-What Have We Learned?","volume":"38","author":"Ghilardi","year":"2020","journal-title":"Annu. Rev. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.3389\/fimmu.2020.01444","article-title":"NLRP3 Inflammasome Activation in Cancer: A Double-Edged Sword","volume":"11","author":"Hamarsheh","year":"2020","journal-title":"Front. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: Gene Set Variation Analysis for Microarray and RNA-Seq Data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative Molecular Characterization of Malignant Pleural Mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"B21","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1158\/2159-8290.CD-16-0127","article-title":"Role of KEAP1\/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance","volume":"7","author":"Jeong","year":"2017","journal-title":"Cancer Discov."},{"key":"B22","doi-asserted-by":"publisher","first-page":"7411","DOI":"10.3390\/ijms22147411","article-title":"Somatic Mutations in Circulating Cell-free DNA and Risk for Hepatocellular Carcinoma in Hispanics","volume":"22","author":"Jiao","year":"2021","journal-title":"Ijms"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.4049\/jimmunol.2000612","article-title":"Dynamic Roles for IL-2-STAT5 Signaling in Effector and Regulatory CD4+ T Cell Populations","volume":"205","author":"Jones","year":"2020","journal-title":"J.I."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1200\/JCO.2017.76.6394","article-title":"Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline","volume":"36","author":"Kindler","year":"2018","journal-title":"Jco"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.3892\/or.13.6.1153","article-title":"Relative Expression Levels of Th1 and Th2 Cytokine mRNA Are Independent Prognostic Factors in Patients with Ovarian Cancer","volume":"13","author":"Kusuda","year":"2005","journal-title":"Oncol. Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R Package for Weighted Correlation Network Analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"B27","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1111\/imm.12216","article-title":"Transcriptional Regulation of T Helper Type 2 Differentiation","volume":"141","author":"Lee","year":"2014","journal-title":"Immunology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for Analysis of Tumor-Infiltrating Immune Cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1164\/rccm.201608-1755CI","article-title":"Checkpoint Blockade in Lung Cancer and Mesothelioma","volume":"196","author":"Lievense","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1726","DOI":"10.3390\/cancers11111726","article-title":"STAT5A and STAT5B-Twins with Different Personalities in Hematopoiesis and Leukemia","volume":"11","author":"Maurer","year":"2019","journal-title":"Cancers"},{"key":"B31","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1080\/10408398.2017.1358139","article-title":"Immune Modulation by Curcumin: The Role of Interleukin-10","volume":"59","author":"Mollazadeh","year":"2019","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"B32","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1186\/s12943-018-0900-3","article-title":"Role of the NLRP3 Inflammasome in Cancer","volume":"17","author":"Moossavi","year":"2018","journal-title":"Mol. Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1158\/1078-0432.CCR-08-1980","article-title":"Evidence of Systemic Th2-Driven Chronic Inflammation in Patients with Metastatic Melanoma","volume":"15","author":"Nevala","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1016\/S1470-2045(20)30462-9","article-title":"Durvalumab with First-Line Chemotherapy in Previously Untreated Malignant Pleural Mesothelioma (DREAM): a Multicentre, Single-Arm, Phase 2 Trial with a Safety Run-In","volume":"21","author":"Nowak","year":"2020","journal-title":"Lancet Oncol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3755","DOI":"10.1177\/0962280218814556","article-title":"Confidence Intervals for the Mann-Whitney Test","volume":"28","author":"Perme","year":"2019","journal-title":"Stat. Methods Med. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.trecan.2016.10.002","article-title":"Emerging Roles for Eosinophils in the Tumor Microenvironment","volume":"2","author":"Reichman","year":"2016","journal-title":"Trends Cancer"},{"key":"B37","doi-asserted-by":"publisher","first-page":"6939","DOI":"10.7150\/jca.48100","article-title":"NFE2L3 Promotes Malignant Behavior and EMT of Human Hepatocellular Carcinoma (HepG2) Cells via Wnt\/\u03b2-catenin P-athway","volume":"11","author":"Ren","year":"2020","journal-title":"J. Cancer"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers Differential Expression Analyses for RNA-Sequencing and Microarray Studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e20190418","DOI":"10.1084\/jem.20190418","article-title":"Biology and Therapeutic Potential of Interleukin-10","volume":"217","author":"Saraiva","year":"2020","journal-title":"J. Exp. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.athoracsur.2007.06.066","article-title":"Malignant Pleural Mesothelioma: Surgical Management in 285 Patients","volume":"85","author":"Schipper","year":"2008","journal-title":"Ann. Thorac. Surg."},{"key":"B41","doi-asserted-by":"publisher","first-page":"632581","DOI":"10.3389\/fimmu.2021.632581","article-title":"Metabolic Interdependency of Th2 Cell-Mediated Type 2 Immunity and the Tumor Microenvironment","volume":"12","author":"Schreiber","year":"2021","journal-title":"Front. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2998","DOI":"10.3390\/ijms22062998","article-title":"Involvement of IL-4, IL-13 and Their Receptors in Pancreatic Cancer","volume":"22","author":"Shi","year":"2021","journal-title":"Ijms"},{"key":"B43","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.cyto.2015.05.026","article-title":"Targeting of IL-4 and IL-13 Receptors for Cancer Therapy","volume":"75","author":"Suzuki","year":"2015","journal-title":"Cytokine"},{"key":"B44","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41417-020-0183-x","article-title":"Revisiting the Role of CD4+ T Cells in Cancer Immunotherapy-New Insights into Old Paradigms","volume":"28","author":"Tay","year":"2021","journal-title":"Cancer Gene Ther."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1016\/j.jtho.2018.08.2036","article-title":"Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation","volume":"13","author":"Tsao","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1200\/JCO.2003.11.136","article-title":"Phase III Study of Pemetrexed in Combination with Cisplatin versus Cisplatin Alone in Patients with Malignant Pleural Mesothelioma","volume":"21","author":"Vogelzang","year":"2003","journal-title":"Jco"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1126\/science.1117893","article-title":"Structure of the Quaternary Complex of Interleukin-2 with its \u03b1, SS, and \u03b3 C Receptors","volume":"310","author":"Wang","year":"2005","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","first-page":"175883592097142","DOI":"10.1177\/1758835920971421","article-title":"Biomarker-guided Targeted and Immunotherapies in Malignant Pleural Mesothelioma","volume":"12","author":"Yang","year":"","journal-title":"Ther. Adv. Med. Oncol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.3390\/cancers12082310","article-title":"Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma","volume":"12","author":"Yang","year":"","journal-title":"Cancers"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1002\/ijc.32151","article-title":"IL\u201010 Derived from M2 Macrophage Promotes Cancer Stemness via JAK1\/STAT1\/NF\u2010\u03baB\/Notch1 Pathway in Non\u2010small Cell Lung Cancer","volume":"145","author":"Yang","year":"2019","journal-title":"Int. J. Cancer"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1158\/0008-5472.CAN-14-2379","article-title":"Interleukin-5 Facilitates Lung Metastasis by Modulating the Immune Microenvironment","volume":"75","author":"Zaynagetdinov","year":"2015","journal-title":"Cancer Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"4312","DOI":"10.1158\/0008-5472.CAN-14-3590","article-title":"CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer","volume":"75","author":"Zhang","year":"2015","journal-title":"Cancer Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1038\/s41467-021-21254-9","article-title":"Uniform Genomic Data Analysis in the NCI Genomic Data Commons","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat. Commun."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"B55","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1146\/annurev-immunol-030409-101212","article-title":"Differentiation of Effector CD4 T Cell Populations","volume":"28","author":"Zhu","year":"2010","journal-title":"Annu. Rev. Immunol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.805256\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T07:17:20Z","timestamp":1652858240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.805256\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,18]]},"references-count":55,"alternative-id":["10.3389\/fgene.2022.805256"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.805256","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2022,5,18]]},"article-number":"805256"}}