{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:10:05Z","timestamp":1787663405775,"version":"build-2736575974"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"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. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The estrogen-related receptor family genes (ERRs), including ESRRA, ESRRB, and ESRRG, have been implicated in a few tumors, exhibiting distinct roles through diverse mechanisms. The purpose of our research is to explore the commonalities and underlying mechanism of ERRs in malignancies from a pan-cancer perspective and to validate the role and mechanisms of ESRRG in gallbladder cancer (GBC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We leveraged public databases such as TCGA and GTEx to systematically investigate the potential functions of ERRs in malignancies. ESRRG expression was analyzed through immunohistochemical staining in gallbladder cancer and cholecystitis tissues. For functional validation, ESRRG was knocked down in GBC cell lines, followed by CCK-8, colony formation, scratch wound healing, Transwell migration, and invasion assays. Western blot,  qPCR, and immunofluorescence were performed to evaluate the relationship between ESRRG, PD-L1, and CD8<jats:sup>+<\/jats:sup> T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to adjacent normal tissues, ESRRA is overexpressed in most tumors, ESRRB is generally underexpressed, and ESRRG exhibits significant expression alterations across various tumors. All three ERRs demonstrate significant prognostic value across different cancers. Notably, the strong associations of ERRs with key immunological features\u2014stromal scores, immune cell infiltration, microsatellite instability (MSI), and tumor mutational burden (TMB)\u2014suggest their involvement in immune evasion and their potential utility in guiding immunotherapy strategies. All three ERRs display a positive correlation with advanced tumor stages in cholangiocarcinoma (CHOL). Specifically, in CHOL, ESRRG expression is closely associated with lymphatic metastasis, poorer overall survival, reduced immune infiltration, elevated PD-L1 expression, epithelial-mesenchymal transition (EMT), and DNA damage response. In GBC tissues, we subsequently confirmed that ESRRG expression positively correlates with pathological staging and PD-L1 expression, while negatively correlating with prognosis and CD8<jats:sup>+<\/jats:sup> T cell infiltration. Knockdown of ESRRG in gallbladder cancer cells results in decreased proliferation, migration, and invasion. Moreover, the expression of PD-L1, MSH2, BRCA1, MMP2, and VIMENTIN decreased with ESRRG knockdown. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our pan-cancer analysis reveals ERRs as critical regulators of tumor immunity and progression, with ESRRG emerging as a key oncogenic driver in GBC. The mechanistic link between ESRRG and PD-L1\/EMT suggests its potential as a therapeutic target to enhance immunotherapy efficacy. These findings underscore the need for tissue-specific targeting strategies for ERR family members in precision oncology.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1525635","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T04:11:35Z","timestamp":1745813495000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Deciphering ERR family genes as prognostic and immunological biomarkers through pan-cancer analysis with validation in gallbladder cancer"],"prefix":"10.3389","volume":"15","author":[{"given":"Wanwan","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijia","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingmei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiqin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daozhen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe6474","article-title":"Pan-cancer single-cell landscape of tumor-infiltrating T cells","volume":"374","author":"Zheng","year":"2021","journal-title":"Sci (New York NY)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.205784","article-title":"Unraveling the unfolded protein response signature: implications for tumor immune microenvironment heterogeneity and clinical prognosis in stomach cancer","volume":"16","author":"Ouyang","year":"2024","journal-title":"Aging (Albany NY)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"677","DOI":"10.21037\/atm-21-853","article-title":"A comprehensive pan-cancer analysis of cd274 gene amplification, tumor mutation burden, microsatellite instability, and pd-L1 expression in chinese cancer patients","volume":"9","author":"Gao","year":"2021","journal-title":"Ann Transl Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.758288","article-title":"Single-cell transcriptomic analysis reveals a tumor-reactive T cell signature associated with clinical outcome and immunotherapy response in melanoma","volume":"12","author":"Yan","year":"2021","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-008547","article-title":"Oral pd-L1 inhibitor gs-4224 selectively engages pd-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors","volume":"12","author":"Odegard","year":"2024","journal-title":"J Immunother Cancer"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-023-00780-9","article-title":"Transcription initiation by the errs: no ligand but two activation pathways","volume":"33","author":"Gigu\u00e8re","year":"2023","journal-title":"Cell Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2147\/cmar.S182466","article-title":"Key regulator of cellular metabolism, estrogen-related receptor A, a new therapeutic target in endocrine-related gynecological tumor","volume":"10","author":"Liu","year":"2018","journal-title":"Cancer Manag Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1158\/2159-8290.Cd-22-0244","article-title":"Discovery of targets for immune-metabolic antitumor drugs identifies estrogen-related receptor alpha","volume":"13","author":"Sahu","year":"2023","journal-title":"Cancer Discov"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14344","article-title":"Estrogen-related receptor-A Promotes gallbladder cancer development by enhancing the transcription of nectin-4","volume":"111","author":"Wang","year":"2020","journal-title":"Cancer Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210986","article-title":"Orphan nuclear receptor estrogen-related receptor-beta suppresses in vitro and in vivo growth of prostate cancer cells via P21(Waf1\/cip1) induction and as a potential therapeutic target in prostate cancer","volume":"27","author":"Yu","year":"2008","journal-title":"Oncogene"},{"key":"B11","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/s41419-020-02838-7","article-title":"Neddylation negatively regulates err\u03b2 Expression to promote breast cancer tumorigenesis and progression","volume":"11","author":"Naik","year":"2020","journal-title":"Cell Death Dis"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e213","DOI":"10.1038\/emm.2015.115","article-title":"Estrogen-related receptor \u0393 Is upregulated in liver cancer and its inhibition suppresses liver cancer cell proliferation via induction of P21 and P27","volume":"48","author":"Kim","year":"2016","journal-title":"Exp Mol Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2022.55.11.089","article-title":"Dn200434, an orally available inverse agonist of estrogen-related receptor \u0393, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma","volume":"55","author":"Kim","year":"2022","journal-title":"BMB Rep"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1177\/1533033821992083","article-title":"Comprehensive analysis of esrra in endometrial cancer","volume":"20","author":"Wang","year":"2021","journal-title":"Technol Cancer Res Treat"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2021.12252","article-title":"Pi3k\/akt phosphorylation activates err\u03b1 by upregulating pgc\u22121\u03b1 and pgc\u22121\u03b2 in gallbladder cancer","volume":"24","author":"Wang","year":"2021","journal-title":"Mol Med Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbac558","article-title":"Gsca: an integrated platform for gene set cancer analysis at genomic, pharmacogenomic and immunogenomic levels","volume":"24","author":"Liu","year":"2023","journal-title":"Brief Bioinform"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty411","article-title":"Gscalite: A web server for gene set cancer analysis","volume":"34","author":"Liu","year":"2018","journal-title":"Bioinformatics"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2056-8","article-title":"Peripheral T cell expansion predicts tumour infiltration and clinical response","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apcsb.2024.02.004","article-title":"Immunotherapy guided precision medicine in solid tumors","volume":"140","author":"Mehrotra","year":"2024","journal-title":"Adv Protein Chem Struct Biol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1186\/s12935-021-02049-w","article-title":"Multi-omics analysis reveals prognostic value of tumor mutation burden in hepatocellular carcinoma","volume":"21","author":"Xu","year":"2021","journal-title":"Cancer Cell Int"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.18632\/aging.102817","article-title":"Identification of prognostic immune-related genes in the tumor microenvironment of endometrial cancer","volume":"12","author":"Chen","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.7150\/thno.44877","article-title":"A novel mir-1291-err\u03b1-cpt1c axis modulates tumor cell proliferation, metabolism and tumorigenesis","volume":"10","author":"Chen","year":"2020","journal-title":"Theranostics"},{"key":"B23","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1007\/s12032-024-02329-1","article-title":"Estrogen-related receptor alpha (Err\u03b1) promotes the migration, invasion and angiogenesis of breast cancer stem cell-like cells","volume":"41","author":"Muduli","year":"2024","journal-title":"Med Oncol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1186\/s12967-023-04347-5","article-title":"Esrrg-pkm2 axis reprograms metabolism to suppress esophageal squamous carcinoma progression and enhance anti-pd-1 therapy efficacy","volume":"21","author":"Wang","year":"2023","journal-title":"J Transl Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1186\/s12885-020-07067-x","article-title":"Sophoridine exerts tumor-suppressive activities via promoting esrrg-mediated B-catenin degradation in gastric cancer","volume":"20","author":"Peng","year":"2020","journal-title":"BMC Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nri3405","article-title":"Molecular mechanisms of T cell co-stimulation and co-inhibition","volume":"13","author":"Chen","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz116","article-title":"Esmo recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with pd-1\/pd-L1 expression and tumour mutational burden: A systematic review-based approach","volume":"30","author":"Luchini","year":"2019","journal-title":"Ann Oncol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s13045-022-01294-4","article-title":"Exploring immunotherapy in colorectal cancer","volume":"15","author":"Weng","year":"2022","journal-title":"J Hematol Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/imt2.36","article-title":"Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform","volume":"1","author":"Shen","year":"2022","journal-title":"iMeta"},{"key":"B30","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.cell.2018.02.052","article-title":"An integrated tcga pan-cancer clinical data resource to drive high-quality survival outcome analytics","volume":"173","author":"Liu","year":"2018","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring tumour purity and stromal and immune cell admixture from expression data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat Commun"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-17-0307","article-title":"Timer: A web server for comprehensive analysis of tumor-infiltrating immune cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.687975","article-title":"Iobr: multi-omics immuno-oncology biological research to decode tumor microenvironment and signatures","volume":"12","author":"Zeng","year":"2021","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1097403","article-title":"Ncapg2 could be an immunological and prognostic biomarker: from pan-cancer analysis to pancreatic cancer validation","volume":"14","author":"Wang","year":"2023","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"4740","DOI":"10.1038\/s41467-020-18514-5","article-title":"The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution","volume":"11","author":"Ballhausen","year":"2020","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-19-1372","article-title":"Noninvasive detection of microsatellite instability and high tumor mutation burden in cancer patients treated with pd-1 blockade","volume":"25","author":"Georgiadis","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq537","article-title":"The genemania prediction server: biological network integration for gene prioritization and predicting gene function","volume":"38","author":"Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.925537","article-title":"A pan-cancer analysis of the expression of stat family genes in tumors and their relationship to the tumor microenvironment","volume":"12","author":"Zhou","year":"2022","journal-title":"Front Oncol"},{"key":"B40","volume-title":"Ajcc Cancer Staging Manual 8th Edition","author":"Amin SBE","year":"2017"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2016.104","article-title":"Altered cardiovascular function at birth in growth-restricted preterm lambs","volume":"80","author":"Polglase","year":"2016","journal-title":"Pediatr Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.02.036","article-title":"Fgf19\/fgfr4-mediated elevation of etv4 facilitates hepatocellular carcinoma metastasis by upregulating pd-L1 and ccl2","volume":"79","author":"Xie","year":"2023","journal-title":"J Hepatol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1525635\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T04:11:36Z","timestamp":1745813496000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1525635\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,28]]},"references-count":42,"alternative-id":["10.3389\/fonc.2025.1525635"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1525635","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,28]]},"article-number":"1525635"}}