{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:04:34Z","timestamp":1788887074680,"version":"build-2803163510"},"reference-count":47,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cervical cancer is the most frequent malignancy of the female genital tract and is associated with persistent infection of the uterine cervix with high\u2010risk human papillomaviruses (HPV). The two HPV oncoproteins, E6 and E7, cooperatively immortalize cervical cells and are essential but insufficient for inducing tumorigenicity. During the progression of HPV\u2010associated cervical dysplasia to carcinoma, the cellular telomerase reverse transcriptase (TERT) gene is activated and the TERC gene amplified. We questioned whether these increases in telomerase components might mediate the acquisition of the tumorigenic phenotype. We therefore transduced the TERT and TERC genes into E6\/E7 immortalized keratinocytes that were anchorage\u2010dependent and nontumorigenic. The resultant cells showed a profound morphological change characteristic of epithelial\u2010mesenchymal transition\u00a0as well as a corresponding increase in expression of vimentin, N\u2010cadherin, Zinc finger E\u2010Box binding homeobox 1, snail family transcriptional repressor 1\u00a0and matrix Metallopeptidase 2 and decrease in keratin and E\u2010cadherin. More important, the transduced cells were now anchorage\u2010independent and formed tumors in immunodeficient mice. Our findings indicate that overexpression of the telomerase holoenzyme in HPV\u2010immortalized cells is sufficient to induce the complete transformed phenotype.<\/jats:p>","DOI":"10.1002\/jmv.28681","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T12:28:15Z","timestamp":1679056095000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Overexpression of the telomerase holoenzyme induces EMT and tumorigenesis of HPV\u2010immortalized keratinocytes"],"prefix":"10.1002","volume":"95","author":[{"given":"Aibing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology Georgetown University Medical School Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pathology Georgetown University Medical School Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1394-9720","authenticated-orcid":false,"given":"Ewa","family":"Krawczyk","sequence":"additional","affiliation":[{"name":"Department of Pathology Georgetown University Medical School Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuanjie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology Ohio State University Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Simic","sequence":"additional","affiliation":[{"name":"Department of Pathology Georgetown University Medical School Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pathology Georgetown University Medical School Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology Georgetown University Medical School Washington DC USA"},{"name":"Department of Pathology Ohio State University Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Schlegel","sequence":"additional","affiliation":[{"name":"Department of Pathology Georgetown University Medical School Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8338-6313","authenticated-orcid":false,"given":"Hang","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Pathology Georgetown University Medical School Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30157-4"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2011.04.005"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.16.1.1-17.2003"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1987.tb04849.x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2008.10.006"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1989.tb08570.x"},{"key":"e_1_2_9_9_1","first-page":"320","article-title":"Molecular pathways in the development of hpv\u2010induced cervical cancer","volume":"20","author":"Bonab FR","year":"2021","journal-title":"EXCLI Journal"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-019-0099-1"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/v9070180"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","unstructured":"SoderAI HoareSF MuirS GoingJJ ParkinsonEK KeithN. Ampli\u00aecation increased dosage and in situ expression of the telomerase RNA gene in human cancer.\u00a01997.","DOI":"10.1038\/sj.onc.1201066"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63498-0"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52195-5"},{"key":"e_1_2_9_15_1","first-page":"4235","volume-title":"Cellular and Molecular Life Sciences","author":"Akincilar SC","year":"2021"},{"key":"e_1_2_9_16_1","unstructured":"BrennerKA. A noncanonical function of the telomerase RNA component in a noncanonical function of the telomerase RNA component in human embryonic stem cells human embryonic stem cells. 2019.https:\/\/openscholarship.wustl.edu\/art_sci_etds"},{"key":"e_1_2_9_17_1","unstructured":"StewartSA HahnWC O'connorBF et al. Telomerase contributes to tumorigenesis by a telomere length\u2010independent mechanism.\u00a0n.d.\u00a0www.pnas.orgcgidoi10.1073pnas.182407599"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021108647"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.09.007"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910590514"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001574"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207148"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1435900100"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1476206"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.21.10685-10691.2002"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(82)90400-7"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3758"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11684-018-0656-6"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2014.2189"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e05-09-0903"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0296-200"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400359"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222413543"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"issue":"11","key":"e_1_2_9_36_1","first-page":"6389","article-title":"Human telomerase reverse transcriptase is a promising target for cancer inhibition in squamous cell carcinomas","volume":"34","author":"Park Y\u2010J","year":"2014","journal-title":"Anticancer Res"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2621"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209808"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2008.00756.x"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2016.11.003"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906357106"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40291-018-0336-x"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22064"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.3.669"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.12.5559-5566.2001"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/v14071483"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01377-10"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003284"}],"container-title":["Journal of Medical Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmv.28681","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmv.28681","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T07:56:45Z","timestamp":1692259005000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmv.28681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,31]]},"references-count":47,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1002\/jmv.28681"],"URL":"https:\/\/doi.org\/10.1002\/jmv.28681","archive":["Portico"],"relation":{},"ISSN":["0146-6615","1096-9071"],"issn-type":[{"value":"0146-6615","type":"print"},{"value":"1096-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,31]]},"assertion":[{"value":"2023-02-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e28681"}}