{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:04:43Z","timestamp":1790229883658,"version":"4.1.0"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"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>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the biological significance of ten\u2013eleven translocation 1 (TET1) in cervical cancer and its association with PTEN\u2013PI3K\/AKT\/mTOR signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Publicly available bulk and single-cell transcriptomic datasets were analyzed, with histology-restricted analyses focused on cervical squamous cell carcinoma (SCC). TET1 immunoreactivity was assessed in five paired cervical adenocarcinoma and adjacent non-neoplastic tissues using nuclear H-scores. TET1 loss of function was modeled in HeLa cells by shRNA-mediated knockdown, with Bobcat339 used as a complementary TET-family inhibitor. Cellular metabolic activity, clonogenicity, cell-cycle distribution, apoptosis, migration, and invasion were evaluated using CCK-8, colony-formation, flow-cytometric, wound-healing, and Transwell assays. Protein expression and phosphorylation were examined by western blotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SCC-restricted bulk analyses consistently showed lower TET1 expression in cervical SCC than in normal cervical tissues. In TCGA-CESC SCC, TET1 expression was not significantly associated with PTEN expression or the PI3K\u2013AKT\u2013mTOR transcriptional score after multiple-testing correction, whereas an inverse association with the apoptosis score remained significant. Patient-level pseudobulk analysis of 12 SCC cases likewise identified no pathway association that remained significant after false-discovery-rate correction. In five paired cervical adenocarcinoma cases, TET1 nuclear H-scores were lower in all tumor samples than in their matched adjacent tissues, although the difference did not reach statistical significance (exact P\u00a0=\u00a00.0625). In HeLa cells, TET1 depletion increased cellular metabolic activity and clonogenicity, altered cell-cycle distribution, reduced apoptosis, and enhanced migration and invasion. These changes were accompanied by reduced PTEN expression and increased phosphorylation of PI3K, AKT, and mTOR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Reduced TET1 expression was observed in SCC-restricted public cohorts, while TET1 depletion promoted malignant phenotypes in HeLa cells. The accompanying changes in PTEN expression and PI3K\/AKT\/mTOR phosphorylation identify a candidate signaling association that warrants validation through rescue experiments and locus-specific epigenetic studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1963427","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:44:26Z","timestamp":1790228666000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TET1 loss promotes malignant phenotypes in HeLa cells and is associated with altered PTEN\u2013PI3K\/AKT\/mTOR signaling"],"prefix":"10.3389","volume":"16","author":[{"given":"Yan","family":"Liu","sequence":"first","affiliation":[{"name":"Obstetrics and Gynecology, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lujia","family":"Liu","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lusheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Central Laboratory, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Ren","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanle","family":"Meng","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengling","family":"Chen","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Yao","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tumor Pathology of Suzhou","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tumor Pathology of Suzhou","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Tang","sequence":"additional","affiliation":[{"name":"Central Laboratory, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Ma","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology, Wanbei Coal Electric Group General Hospital","place":["Suzhou, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12571","DOI":"10.3390\/ijms222212571","article-title":"Cervical carcinoma: oncobiology and biomarkers","volume":"22","author":"Volkova","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1358\/dot.2022.58.5.3400745","article-title":"Tisotumab vedotin for the treatment of cervical carcinoma","volume":"58","author":"Song","year":"2022","journal-title":"Drugs Today (Barc)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"937","DOI":"10.3390\/v17070937","article-title":"Regulation and deregulation of viral gene expression during high-risk HPV infection","volume":"17","author":"Schichl","year":"2025","journal-title":"Viruses"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2009.02.011","article-title":"Epigenetic alterations in cervical carcinogenesis","volume":"19","author":"Szalm\u00e1s","year":"2009","journal-title":"Semin Cancer Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0260857","article-title":"Genome-wide host methylation profiling of anal and cervical carcinoma","volume":"16","author":"Siegel","year":"2021","journal-title":"PloS One"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0673-7","article-title":"Analysis of Ugandan cervical carcinomas identifies human papillomavirus clade-specific epigenome and transcriptome landscapes","volume":"52","author":"Gagliardi","year":"2020","journal-title":"Nat Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70245","article-title":"Ten-eleven translocation family proteins: structure, biological functions, diseases, and targeted therapy","volume":"6","author":"Liang","year":"2025","journal-title":"MedComm (2020)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1038\/s41392-023-01537-x","article-title":"TET (Ten-eleven translocation) family proteins: structure, biological functions and applications","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduction Targeted Ther"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/2664370","article-title":"High expression of ten eleven translocation 1 is associated with poor prognosis in hepatocellular carcinoma","volume":"2023","author":"Wen","year":"2023","journal-title":"Mediators Inflammation"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14897","article-title":"TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma","volume":"112","author":"Shirai","year":"2021","journal-title":"Cancer Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105611","article-title":"BACH1 is transcriptionally inhibited by TET1 in hepatocellular carcinoma in a microRNA-34a-dependent manner to regulate autophagy and inflammation","volume":"169","author":"Sun","year":"2021","journal-title":"Pharmacol Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2024.2323751","article-title":"TET1 inhibits the migration and invasion of cervical cancer cells by regulating autophagy","volume":"19","author":"Ren","year":"2024","journal-title":"Epigenetics"},{"key":"B13","doi-asserted-by":"publisher","first-page":"719","DOI":"10.3390\/genes11070719","article-title":"PTEN alterations and their role in cancer management: are we making headway on precision medicine","volume":"11","author":"Fusco","year":"2020","journal-title":"Genes (Basel)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-020-00292-w","article-title":"Feedback activation of STAT3 limits the response to PI3K\/AKT\/mTOR inhibitors in PTEN-deficient cancer cells","volume":"10","author":"Wang","year":"2021","journal-title":"Oncogenesis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.3390\/molecules27082431","article-title":"Nigrosporins B, a potential anti-cervical cancer agent, induces apoptosis and protective autophagy in human cervical cancer Ca Ski cells mediated by PI3K\/AKT\/mTOR signaling pathway","volume":"27","author":"Zhang","year":"2022","journal-title":"Molecules"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8900","article-title":"TET1 inhibits gastric cancer growth and metastasis by PTEN demethylation and re-expression","volume":"7","author":"Pei","year":"2016","journal-title":"Oncotarget"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2022.154010","article-title":"PI3K\/Akt\/mTOR signaling pathway in cancer stem cells","volume":"237","author":"Karami Fath","year":"2022","journal-title":"Pathol Res Pract"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107191","article-title":"TET1 facilitates specification of early human lineages including germ cells","volume":"26","author":"Hsu","year":"2023","journal-title":"iScience"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2021.158919","article-title":"TET1 promotes RXR\u03b1 expression and adipogenesis through DNA demethylation","volume":"1866","author":"Qian","year":"2021","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2004.03.013","article-title":"Epigenetic and genetic alternation of PTEN in cervical neoplasm","volume":"93","author":"Cheung","year":"2004","journal-title":"Gynecol Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3892\/br.2014.298","article-title":"Promoter region methylation and loss of protein expression of PTEN and significance in cervical cancer","volume":"2","author":"Qi","year":"2014","journal-title":"BioMed Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/08941939.2022.2162170","article-title":"Foxo3a-mediated DNMT3B impedes cervical cancer cell proliferation and migration capacities through suppressing PTEN promoter methylation","volume":"36","author":"Li","year":"2023","journal-title":"J Invest Surg"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1963427\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:44:27Z","timestamp":1790228667000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1963427\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":22,"alternative-id":["10.3389\/fonc.2026.1963427"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1963427","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]},"article-number":"1963427"}}