{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T17:11:40Z","timestamp":1784740300289,"version":"3.55.0"},"reference-count":50,"publisher":"SAGE Publications","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CBM"],"published-print":{"date-parts":[[2021,8,24]]},"abstract":"<jats:p>BACKGROUND: Stemness factors associated with tumorigenesis in different types of cancers have not been specifically studied in oral tongue SCC (OTSSC). Here, we aimed to quantify expression levels and distribution of KLF4 and SOX2, two relevant stemness factors, in oral SCC including OTSCC samples from different subsites. METHODS AND RESULTS: We determined KLF4 and SOX2 expression levels by immunostaining 35 biopsies of OSCC. Stained wholeslide images were digitized and subjected to automatic cell detection and unbiased quantification using Qupath software. We found statistically significant reduction in KLF4 positive cells density (p= 0.024), and fraction (p= 0.022) in OTSCC from tongue borders compared with other tongue subsites. Instead, quantitative SOX2 analysis did not show differences in expression levels between OTSCC from the borders versus OTSCC developed in others subsites. Notably SOX2 expression was revealed increased in moderately and poorly differentiated OSCC compared with well differentiated ones (positive cells density p= 0.025, fraction p= 0.006). No significant correlation between KLF4 and SOX2 expression was observed, neither in OSCC nor in OTSCC. CONCLUSIONS: KLF4 and SOX2 exhibit opposite expression profiles regarding subsite localization and differentiation level in OSCC. Our study prompts future OTSCC prospective studies looking for clinical prognosis to incorporate detailed subsite information in the analysis.<\/jats:p>","DOI":"10.3233\/cbm-203086","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T13:22:47Z","timestamp":1622553767000},"page":"37-48","source":"Crossref","is-referenced-by-count":2,"title":["Quantitative analysis of KLF4 and SOX2 expression in oral carcinomas reveals independent association with oral tongue subsite location and histological grade"],"prefix":"10.1177","volume":"32","author":[{"given":"Mar\u00eda Luisa","family":"Paparella","sequence":"first","affiliation":[{"name":"School of Dentistry, Oral Pathology Department, Surgical Pathology Laboratory, University of Buenos Aires, Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario Martin","family":"Ferri","sequence":"additional","affiliation":[{"name":"Instituto de Fisiolog\u00eda, Biolog\u00eda Molecular y Neurociencias (IFIBYNE-UBACONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires y Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krissya Mar\u00eda","family":"Villegas","sequence":"additional","affiliation":[{"name":"School of Dentistry, Oral Pathology Department, Surgical Pathology Laboratory, University of Buenos Aires, Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Rosa","family":"Raimondi","sequence":"additional","affiliation":[{"name":"School of Dentistry, Oral Pathology Department, Surgical Pathology Laboratory, University of Buenos Aires, Buenos Aires, Argentina"},{"name":"Instituto de Fisiolog\u00eda, Biolog\u00eda Molecular y Neurociencias (IFIBYNE-UBACONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires y Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CONICET), Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/CBM-203086_ref1","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"International Journal of Cancer"},{"key":"10.3233\/CBM-203086_ref2","first-page":"7","article-title":"Cancer statistics, 2018","volume":"68","author":"Siegel","year":"2018","journal-title":"CA: A Cancer Journal for Clinicians"},{"key":"10.3233\/CBM-203086_ref3","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s00432-006-0111-y","article-title":"Carcinoma of tongue and the buccal mucosa represent different biological subentities of the oral carcinoma","volume":"132","author":"Sathyan","year":"2006","journal-title":"Journal of Cancer Research and Clinical Oncology"},{"key":"10.3233\/CBM-203086_ref4","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.oraloncology.2006.11.012","article-title":"Squamous cell carcinomas arising from different types of oral epithelia differ in their tumor and patient characteristics and survival","volume":"43","author":"Rautava","year":"2007","journal-title":"Oral Oncology"},{"key":"10.3233\/CBM-203086_ref5","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/s41416-018-0233-4","article-title":"A review of the most promising biomarkers for early diagnosis and prognosis prediction of tongue squamous cell carcinoma","volume":"119","author":"Hussein","year":"2018","journal-title":"British Journal of Cancer"},{"key":"10.3233\/CBM-203086_ref6","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.oraloncology.2008.06.002","article-title":"Global epidemiology of oral and oropharyngeal cancer","volume":"45","author":"Warnakulasuriya","year":"2009","journal-title":"Oral Oncology"},{"key":"10.3233\/CBM-203086_ref8","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.oraloncology.2017.02.019","article-title":"Rising incidence of oral tongue cancer among white men and women in the United States, 1973\u20132012","volume":"67","author":"Tota","year":"2017","journal-title":"Oral Oncology"},{"key":"10.3233\/CBM-203086_ref9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ejca.2017.05.026","article-title":"Global incidence of oral and oropharynx cancer in patients younger than 45 years versus older patients: a systematic review","volume":"82","author":"Hussein","year":"2017","journal-title":"European Journal of Cancer (Oxford, England: 1990)"},{"key":"10.3233\/CBM-203086_ref10","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.oraloncology.2010.06.008","article-title":"Prognostic evaluation of oral tongue cancer: means, markers and perspectives (II)","volume":"46","author":"Bello","year":"2010","journal-title":"Oral Oncology"},{"key":"10.3233\/CBM-203086_ref11","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/cncr.23183","article-title":"Poor prognosis in patients with stage I and II oral tongue squamous cell carcinoma","volume":"112","author":"Rusthoven","year":"2008","journal-title":"Cancer"},{"key":"10.3233\/CBM-203086_ref12","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1093\/pcmedi\/pbz016","article-title":"Targeting cancer stem cells in squamous cell carcinoma","volume":"2","author":"Demeng","year":"2019","journal-title":"Precision Clinical Medicine"},{"key":"10.3233\/CBM-203086_ref13","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1177\/0022034518772278","article-title":"Head and neck cancer in the new era of precision medicine","volume":"97","author":"N\u00f6r","year":"2018","journal-title":"Journal of Dental Research"},{"key":"10.3233\/CBM-203086_ref14","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1056\/NEJMoa1602252","article-title":"Nivolumab for recurrent squamous-cell carcinoma of the head and neck","volume":"375","author":"Ferris","year":"2016","journal-title":"New England Journal of Medicine"},{"key":"10.3233\/CBM-203086_ref15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour heterogeneity and resistance to cancer therapies","volume":"15","author":"Dagogo-Jack","year":"2018","journal-title":"Nature Reviews Clinical Oncology"},{"key":"10.3233\/CBM-203086_ref16","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/jcp.28963","article-title":"The molecular markers of cancer stem cells in head and neck tumors","volume":"235","author":"Yu","year":"2020","journal-title":"Journal of Cellular Physiology"},{"key":"10.3233\/CBM-203086_ref17","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"10.3233\/CBM-203086_ref18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrc1780","article-title":"KLF4, p21 and context-dependent opposing forces in cancer","volume":"6","author":"Rowland","year":"2006","journal-title":"Nat.Rev.Cancer"},{"key":"10.3233\/CBM-203086_ref19","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.gene.2017.02.025","article-title":"Kr\u00fcppel-like factor 4 (KLF4): what we currently know","volume":"611","author":"Ghaleb","year":"2017","journal-title":"Gene"},{"key":"10.3233\/CBM-203086_ref20","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nrc3582","article-title":"Kr\u00fcppel-like factors in cancer","volume":"13","author":"Tetreault","year":"2013","journal-title":"Nature Reviews Cancer"},{"key":"10.3233\/CBM-203086_ref21","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/j.1349-7006.2011.01859.x","article-title":"Persistent Kr\u00fcppel-like factor 4 expression predicts progression and poor prognosis of head and neck squamous cell carcinoma","volume":"102","author":"Tai","year":"2011","journal-title":"Cancer Science"},{"key":"10.3233\/CBM-203086_ref22","doi-asserted-by":"crossref","first-page":"44480","DOI":"10.18632\/oncotarget.6256","article-title":"The janus-faced roles of Kr\u00fcppel-like factor 4 in oral squamous cell carcinoma cells","volume":"6","author":"Li","year":"2015","journal-title":"Oncotarget"},{"key":"10.3233\/CBM-203086_ref23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.stem.2012.12.007","article-title":"The sox family of transcription factors: versatile regulators of stem and progenitor cell fate","volume":"12","author":"Sarkar","year":"2013","journal-title":"Cell Stem Cell"},{"key":"10.3233\/CBM-203086_ref24","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.semcancer.2019.08.007","article-title":"SOX2 in development and cancer biology","volume":"67","author":"Novak","year":"2020","journal-title":"Seminars in Cancer Biology"},{"key":"10.3233\/CBM-203086_ref25","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1634\/stemcells.2008-0611","article-title":"Cell lineage mapping of taste bud cells and keratinocytes in the mouse tongue and soft palate","volume":"27","author":"Okubo","year":"2009","journal-title":"Stem Cells"},{"key":"10.3233\/CBM-203086_ref27","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.2353\/ajpath.2006.050847","article-title":"Rapid development of salivary gland carcinomas upon conditional expression of K-ras driven by the cytokeratin 5 promoter","volume":"168","author":"Raimondi","year":"2006","journal-title":"Am.J.Pathol."},{"key":"10.3233\/CBM-203086_ref28","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Scientific Reports"},{"key":"10.3233\/CBM-203086_ref29","doi-asserted-by":"crossref","first-page":"e82","DOI":"10.1038\/bcj.2012.27","article-title":"Aberrant expression and biological significance of Sox2, an embryonic stem cell transcriptional factor, in ALK-positive anaplastic large cell lymphoma","volume":"2","author":"Gelebart","year":"2012","journal-title":"Blood Cancer Journal"},{"key":"10.3233\/CBM-203086_ref30","doi-asserted-by":"crossref","first-page":"521","DOI":"10.4049\/jimmunol.1101530","article-title":"Kr\u00fcppel-like factors in lymphocyte biology","volume":"188","author":"Hart","year":"2012","journal-title":"The Journal of Immunology"},{"key":"10.3233\/CBM-203086_ref31","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1172\/JCI28521","article-title":"Epidermal barrier formation and recovery in skin disorders","volume":"116","author":"Segre","year":"2006","journal-title":"J.Clin.Invest"},{"key":"10.3233\/CBM-203086_ref32","unstructured":"I.K. Shibata Masaki, Chiba Tadashige, Matsuoka Takanori, Mihara Nozomi, Kawashiri Shuichi, Kr\u00fcppel-like factors 4 and 5 expression and their involvement in differentiation of oral carcinomas, Int J Clin Exp Pathol 8 (2015), 3701\u20133709."},{"key":"10.3233\/CBM-203086_ref33","first-page":"838632","article-title":"CD163+ tumor-associated macrophages correlated with poor prognosis and cancer stem cells in oral squamous cell carcinoma","volume":"2014","author":"KF","year":"2014","journal-title":"BioMed Research International"},{"key":"10.3233\/CBM-203086_ref34","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00403-010-1101-0","article-title":"The role of KLF4 in UVB-induced murine skin tumor development and its correlation with cyclin D1, p53, and p21(Waf1\/Cip1) in epithelial tumors of the human skin","volume":"303","author":"Choi","year":"2011","journal-title":"Arch.Dermatol.Res."},{"key":"10.3233\/CBM-203086_ref35","doi-asserted-by":"crossref","first-page":"777","DOI":"10.4161\/cbt.7.5.5768","article-title":"Nuclear Kr\u00fcppel-like factor 4 expression is associated with human skin squamous cell carcinoma progression and metastasis","volume":"7","author":"Chen","year":"2008","journal-title":"Cancer Biology and Therapy"},{"key":"10.3233\/CBM-203086_ref36","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.3892\/ol.2015.4047","article-title":"Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma","volume":"11","author":"Yoshihama","year":"2016","journal-title":"Oncology Letters"},{"key":"10.3233\/CBM-203086_ref37","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1158\/2159-8290.CD-12-0537","article-title":"Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers","volume":"3","author":"Pickering","year":"2013","journal-title":"Cancer Discovery"},{"key":"10.3233\/CBM-203086_ref38","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/gb-2003-4-9-117","article-title":"Comparing protein abundance and mRNA expression levels on a genomic scale","volume":"4","author":"Greenbaum","year":"2003","journal-title":"Genome Biology"},{"key":"10.3233\/CBM-203086_ref39","doi-asserted-by":"crossref","first-page":"24799","DOI":"10.1038\/srep24799","article-title":"Cross-tissue analysis of gene and protein expression in normal and cancer tissues","volume":"6","author":"Kosti","year":"2016","journal-title":"Scientific Reports"},{"key":"10.3233\/CBM-203086_ref40","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1001\/archoto.2012.1792","article-title":"Changing trends in smoking and alcohol consumption in patients with oral cancer treated at Memorial Sloan-Kettering Cancer Center from 1985 to 2009","volume":"138","author":"Montero","year":"2012","journal-title":"Archives of Otolaryngology \u2013 Head and Neck Surgery"},{"key":"10.3233\/CBM-203086_ref41","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s10555-007-9082-y","article-title":"Metastasis of squamous cell carcinoma of the oral tongue","volume":"26","author":"Sano","year":"2007","journal-title":"Cancer and Metastasis Reviews"},{"key":"10.3233\/CBM-203086_ref42","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/j.1600-0714.2009.00845.x","article-title":"Oral cancer over four decades: epidemiology, trends, histology, and survival by anatomical sites","volume":"39","author":"Zini","year":"2010","journal-title":"Journal of Oral Pathology and Medicine"},{"key":"10.3233\/CBM-203086_ref43","first-page":"211","article-title":"Epidemiological and histopathological aspects of tongue squamous cell carcinomas-retrospective study","volume":"44","author":"Ion Ciuc\u0103 M\u0103r\u0103\u015fescu","year":"2018","journal-title":"Current Health Sciences Journal"},{"key":"10.3233\/CBM-203086_ref44","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1093\/carcin\/bgt349","article-title":"Impairing squamous differentiation by Klf4 deletion is sufficient to initiate tongue carcinoma development upon K-Ras activation in mice","volume":"35","author":"Abrigo","year":"2014","journal-title":"Carcinogenesis"},{"key":"10.3233\/CBM-203086_ref45","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/jop.12307","article-title":"Oral-specific ablation of Klf4 disrupts epithelial terminal differentiation and increases premalignant lesions and carcinomas upon chemical carcinogenesis","volume":"44","author":"Paparella","year":"2015","journal-title":"Journal of Oral Pathology & Medicine"},{"key":"10.3233\/CBM-203086_ref46","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1038\/ncb1314","article-title":"The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene","volume":"7","author":"Rowland","year":"2005","journal-title":"Nat.Cell Biol."},{"key":"10.3233\/CBM-203086_ref47","first-page":"1233","article-title":"Oct3\/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma \u2013 PubMed","author":"Wang","year":"2009","journal-title":"Anticancer Res"},{"key":"10.3233\/CBM-203086_ref48","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1016\/j.molonc.2015.05.006","article-title":"Loss of SOX2 expression induces cell motility via vimentin up-regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma","volume":"9","author":"Bayo","year":"2015","journal-title":"Molecular Oncology"},{"key":"10.3233\/CBM-203086_ref49","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1755-8166-7-5","article-title":"An evaluation of SOX2 and hTERC gene amplifications as screening markers in oral and oropharyngeal squamous cell carcinomas","volume":"7","author":"Kokalj Voka\u010d","year":"2014","journal-title":"Molecular Cytogenetics"},{"key":"10.3233\/CBM-203086_ref50","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/S1368-8375(02)00142-2","article-title":"Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer","volume":"39","author":"O-charoenrat","year":"2003","journal-title":"Oral Oncology"},{"key":"10.3233\/CBM-203086_ref51","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1034\/j.1600-0714.2002.310406.x","article-title":"Prediction of delayed neck metastasis in patients with stage I\/II squamous cell carcinoma of the tongue","volume":"31","author":"Okamoto","year":"2002","journal-title":"Journal of Oral Pathology and Medicine"},{"key":"10.3233\/CBM-203086_ref52","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/S1368-8375(00)00042-7","article-title":"Early stage carcinoma of oral tongue: prognostic factors for local control and survival","volume":"36","author":"Al-Rajhi","year":"2000","journal-title":"Oral Oncology"}],"container-title":["Cancer Biomarkers"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/CBM-203086","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T14:08:14Z","timestamp":1777385294000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/CBM-203086"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,24]]},"references-count":50,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.3233\/cbm-203086","relation":{},"ISSN":["1875-8592","1574-0153"],"issn-type":[{"value":"1875-8592","type":"electronic"},{"value":"1574-0153","type":"print"}],"subject":[],"published":{"date-parts":[[2021,8,24]]}}}