{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T10:58:31Z","timestamp":1771498711368,"version":"3.50.1"},"reference-count":115,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"The National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE032212"],"award-info":[{"award-number":["R01DE032212"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"The National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE024964"],"award-info":[{"award-number":["R01DE024964"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objective: Human papillomavirus (HPV) represents the most widespread sexually transmitted infection globally, with high-risk strains such as HPV16 driving a rising incidence of oropharyngeal squamous cell carcinoma (OPSCC), particularly in developed countries like the United States and United Kingdom. In the U.S., HPV16-associated OPSCC has surpassed cervical cancer as the most common HPV-related malignancy. Despite the availability of preventive vaccines, uptake remains suboptimal among adolescents and shifting sexual behaviors have contributed to increased disease burden. Early detection remains a major clinical challenge due to the absence of defined precursor lesions and the extended latency between viral exposure and disease onset. Most patients present with advanced-stage disease and no prior clinical history of pre-malignancy, limiting access to early-stage samples and hindering biomarker discovery. Methods: To address these limitations, we developed an in vitro HPV16 oral cancer model, using the three-dimensional organotypic raft culture system that simulates the progression of HPV16-transfected oral epithelium from precancerous states to malignant phenotypes. Results: Using HPV16-transfected human tonsil keratinocytes, we generated stratified and differentiated epithelia that mimic the biochemical and structural changes observed in vivo. This system enables detailed monitoring of epithelial differentiation, biochemical shifts, viral genome status, and key oncogenic and metabolic markers associated with HPV16-driven OPSCC. By aligning expression profiles with clinical datasets, we validated the model through the measurement of virologic markers linked to infection and progression, as well as tissue markers indicative of carcinogenic transformation. Conclusions: This model offers a promising tool for refining early detection strategies and evaluating potential clinical biomarkers, ultimately aiming to improve diagnostic precision and therapeutic outcomes in HPV-associated OPSCC.<\/jats:p>","DOI":"10.3390\/cancers18040683","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:55:31Z","timestamp":1771494931000},"page":"683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro Model Characterizing Carcinogenic Progression of HPV-Positive Oropharyngeal Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3463-7312","authenticated-orcid":false,"given":"Jesus","family":"Avila Tejeda","sequence":"first","affiliation":[{"name":"Department of Cell and Biological Systems, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sreejata","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Department of Cell and Biological Systems, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8773-3976","authenticated-orcid":false,"given":"Craig","family":"Meyers","sequence":"additional","affiliation":[{"name":"Department of Cell and Biological Systems, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1200\/JCO.2007.14.1713","article-title":"Incidence Trends for Human Papillomavirus\u2013Related and \u2013Unrelated Oral Squamous Cell Carcinomas in the United States","volume":"26","author":"Chaturvedi","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6598","DOI":"10.1158\/0008-5472.CAN-16-0633","article-title":"HPV-Related Oropharynx Cancer in the United Kingdom: An Evolution in the Understanding of Disease Etiology","volume":"76","author":"Schache","year":"2016","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1200\/JCO.2011.36.4596","article-title":"Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States","volume":"29","author":"Chaturvedi","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.hoc.2021.05.004","article-title":"Cancer of the Oropharynx and the Association with Human Papillomavirus","volume":"35","author":"Rettig","year":"2021","journal-title":"Hematol. Clin. North Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"832","DOI":"10.3122\/jabfm.2021.04.200588","article-title":"Human Papillomavirus-Associated Head and Neck Cancer","volume":"34","author":"Nogues","year":"2021","journal-title":"J. Am. Board Fam. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"466","DOI":"10.15585\/mmwr.mm7430a1","article-title":"Vaccination Coverage Among Adolescents Aged 13\u201317 Years\u2014National Immunization Survey-Teen, United States, 2024","volume":"74","author":"Pingali","year":"2025","journal-title":"Morb. Mortal. Wkly. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"26","DOI":"10.32481\/djph.2023.04.008","article-title":"Human Papilloma Virus (HPV) and the Current State of Oropharyngeal Cancer Prevention and Treatment","volume":"9","author":"Gribb","year":"2023","journal-title":"Del. J. Public Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1200\/JCO.2015.61.6995","article-title":"Epidemiology of Human Papillomavirus\u2013Positive Head and Neck Squamous Cell Carcinoma","volume":"33","author":"Gillison","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/lary.25767","article-title":"The epidemiology of the human papillomavirus related to oropharyngeal head and neck cancer","volume":"126","author":"Gooi","year":"2016","journal-title":"Laryngoscope"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104736","DOI":"10.1016\/j.oraloncology.2020.104736","article-title":"Summary from an international cancer seminar focused on human papillomavirus (HPV)-positive oropharynx cancer, convened by scientists at IARC and NCI","volume":"108","author":"Kreimer","year":"2020","journal-title":"Oral Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1158\/1940-6207.CAPR-11-0284","article-title":"Associations between Oral HPV16 Infection and Cytopathology: Evaluation of an Oropharyngeal \u201cPap-Test Equivalent\u201d in High-Risk Populations","volume":"4","author":"Fakhry","year":"2011","journal-title":"Cancer Prev. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3880","DOI":"10.1002\/hed.25923","article-title":"Swallowing-related outcomes associated with late lower cranial neuropathy in long-term oropharyngeal cancer survivors: Cross-sectional survey analysis","volume":"41","author":"Aggarwal","year":"2019","journal-title":"Head Neck"},{"key":"ref_13","first-page":"1066","article-title":"Symptom Burden Associated With Late Lower Cranial Neuropathy in Long-term Oropharyngeal Cancer Survivors","volume":"144","author":"Aggarwal","year":"2018","journal-title":"Arch. Otolaryngol. Neck Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1080\/21645515.2019.1600985","article-title":"HPV-related oropharyngeal cancer: A review on burden of the disease and opportunities for prevention and early detection","volume":"15","author":"Timbang","year":"2019","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1093\/annonc\/mdz138","article-title":"Timing of HPV16-E6 antibody seroconversion before OPSCC: Findings from the HPVC3 consortium","volume":"30","author":"Kreimer","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1002\/cncr.32799","article-title":"Transcervical sonography and human papillomavirus 16 E6 antibodies are sensitive for the detection of oropharyngeal cancer","volume":"126","author":"Kuhs","year":"2020","journal-title":"Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1158\/1055-9965.EPI-17-0220","article-title":"Medical Care Cost of Oropharyngeal Cancer among Texas Patients","volume":"26","author":"Lairson","year":"2017","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1758-3284-4-15","article-title":"The cost burden of oral, oral pharyngeal, and salivary gland cancers in three groups: Commercial insurance, medicare, and medicaid","volume":"4","author":"Jacobson","year":"2012","journal-title":"Head Neck Oncol."},{"key":"ref_19","first-page":"1","article-title":"Human papillomavirus type 45 propagation, infection, and neutralization","volume":"312","author":"Wilson","year":"2003","journal-title":"Virology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/978-1-4939-2013-6_24","article-title":"Native human papillomavirus production, quantification, and infectivity analysis","volume":"1249","author":"Biryukov","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0042-6822(85)90214-4","article-title":"Human papillomavirus type 16 DNA sequence","volume":"145","author":"Seedorf","year":"1985","journal-title":"Virology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1073\/pnas.80.12.3812","article-title":"A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions","volume":"80","author":"Gissmann","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Alam, S., Chatterjee, S., Kang, S.D., Milici, J., Biryukov, J., Chen, H., and Meyers, C. (2020). Anti-Retroviral Protease Inhibitors Regulate Human Papillomavirus 16 Infection of Primary Oral and Cervical Epithelium. Cancers, 12.","DOI":"10.3390\/cancers12092664"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10515","DOI":"10.1128\/JVI.00731-09","article-title":"Tissue-Spanning Redox Gradient-Dependent Assembly of Native Human Papillomavirus Type 16 Virions","volume":"83","author":"Conway","year":"2009","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e01993-17","DOI":"10.1128\/JVI.01993-17","article-title":"Superinfection Exclusion between Two High-Risk Human Papillomavirus Types during a Coinfection","volume":"92","author":"Biryukov","year":"2018","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1126\/science.1323879","article-title":"Biosynthesis of Human Papillomavirus from a Continuous Cell Line Upon Epithelial Differentiation","volume":"257","author":"Meyers","year":"1992","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/S1470-2045(15)00560-4","article-title":"Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): A multicentre cohort study","volume":"17","author":"Huang","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1093\/annonc\/mdu265","article-title":"The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck","volume":"25","author":"Psyrri","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"Johnson","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"vii243","DOI":"10.1093\/annonc\/mdq454","article-title":"The role of human papillomavirus infection in head and neck cancers","volume":"21","year":"2010","journal-title":"Ann. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1002\/cncr.29402","article-title":"Changing prognostic significance of tumor stage and nodal stage in patients with squamous cell carcinoma of the oropharynx in the human papillomavirus era","volume":"121","author":"Keane","year":"2015","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Anayannis, N.V., Schlecht, N.F., Ben-Dayan, M., Smith, R.V., Belbin, T.J., Ow, T.J., Blakaj, D.M., Burk, R.D., Leonard, S.M., and Woodman, C.B. (2018). Association of an intact E2 gene with higher HPV viral load, higher viral oncogene expression, and improved clinical outcome in HPV16 positive head and neck squamous cell carcinoma. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191581"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1158\/0008-5472.CAN-07-2754","article-title":"Type-Dependent Integration Frequency of Human Papillomavirus Genomes in Cervical Lesions","volume":"68","author":"Vinokurova","year":"2008","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1158\/1541-7786.MCR-24-0604","article-title":"Genome Instability Precedes Viral Integration in Human Papillomavirus\u2013Transformed Tonsillar Keratinocytes","volume":"23","author":"Chan","year":"2024","journal-title":"Mol. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5437","DOI":"10.1128\/jvi.70.8.5437-5446.1996","article-title":"Transforming growth factor beta1 induces differentiation in human papillomavirus-positive keratinocytes","volume":"70","author":"Ozbun","year":"1996","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/ijc.23463","article-title":"Gene expression changes during HPV-mediated carcinogenesis: A comparison between an in vitro cell model and cervical cancer","volume":"123","author":"Wan","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_37","first-page":"3709","article-title":"Human cervical and foreskin epithelial cells immortalized by human papillomavirus DNAs exhibit dysplastic differentiation in vivo","volume":"50","author":"Woodworth","year":"1990","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1128\/jvi.64.2.519-526.1990","article-title":"Immortalization and altered differentiation of human keratinocytes in vitro by the E6 and E7 open reading frames of human papillomavirus type 18","volume":"64","author":"Hudson","year":"1990","journal-title":"J. Virol."},{"key":"ref_39","first-page":"167","article-title":"Altered expression of proliferation and differentiation markers in human papillomavirus 16 and 18 immortalized epithelial cells grown in organotypic culture","volume":"140","author":"Merrick","year":"1992","journal-title":"Am. J. Pathol."},{"key":"ref_40","first-page":"673","article-title":"Epithelial cells immortalized by human papilloma-viruses have premalignant characteristics in organotypic culture","volume":"138","author":"Blanton","year":"1991","journal-title":"Am. J. Pathol."},{"key":"ref_41","first-page":"571","article-title":"In vitro differentiation of epithelial cells from cervical neo-plasias resembles in vivo lesions","volume":"5","author":"Rader","year":"1990","journal-title":"Oncogene"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/0090-8258(90)90082-V","article-title":"Human cervical cells immortalized in vitro with oncogenic human papillomavirus DNA differentiate dysplastically in Vivo","volume":"38","author":"Waggoner","year":"1990","journal-title":"Gynecol. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7169","DOI":"10.1073\/pnas.85.19.7169","article-title":"Human papillomavirus type 16 alters human epithelial cell differentiation in vitro","volume":"85","author":"McCance","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1073\/pnas.88.2.570","article-title":"Progression of human papillomavirus type 18-immortalized human keratinocytes to a malignant phenotype","volume":"88","author":"Hurlin","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"R144","DOI":"10.1016\/j.cub.2020.01.004","article-title":"Epidermal structure and differentiation","volume":"30","author":"Moreci","year":"2020","journal-title":"Curr. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"RP100961","DOI":"10.7554\/eLife.100961","article-title":"Molecular and Mechanical Signatures Contributing to Epidermal Differ-entiation and Barrier Formation","volume":"13","author":"Ning","year":"2025","journal-title":"eLife"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1038\/sj.cdd.4401245","article-title":"Terminal differentiation of human epidermal keratinocytes involves mitochondria- and caspase-dependent cell death pathway","volume":"10","author":"Tamiji","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"jcs264242","DOI":"10.1242\/jcs.264242","article-title":"Cell volume regulates terminal differentiation of cultured human epidermal keratinocytes","volume":"138","author":"Zijl","year":"2025","journal-title":"J. Cell Sci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Gutowska-Owsiak, D., Podobas, E.I., Eggeling, C., Ogg, G.S., and de la Serna, J.B. (2020). Addressing Differentiation in Live Human Keratinocytes by Assessment of Membrane Packing Order. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.573230"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/0092-8674(80)90094-X","article-title":"Changes in keratin gene expression during terminal differentiation of the keratinocyte","volume":"19","author":"Fuchs","year":"1980","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/0092-8674(81)90169-0","article-title":"Regulation of terminal differentiation of cultured human keratinocytes by vitamin A","volume":"25","author":"Fuchs","year":"1981","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4068","DOI":"10.1091\/mbc.e10-08-0703","article-title":"Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells","volume":"22","author":"Alam","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Vaidya, M., Dmello, C., and Mogre, S. (2022). Utility of Keratins as Biomarkers for Human Oral Precancer and Cancer. Life, 12.","DOI":"10.3390\/life12030343"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.tripleo.2005.03.033","article-title":"Cytokeratin expression in initial oral mucositis of head and neck irradiated patients","volume":"101","author":"Bonan","year":"2006","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1083\/jcb.132.3.381","article-title":"Onset of re-epithelialization after skin injury correlates with a reorganization of keratin filaments in wound edge keratinocytes: Defining a potential role for keratin 16","volume":"132","author":"Paladini","year":"1996","journal-title":"J. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.humpath.2004.01.021","article-title":"Keratins 8, 10, 13, and 17 are useful markers in the diagnosis of human cervix carcinomas","volume":"35","author":"Carrilho","year":"2004","journal-title":"Hum. Pathol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3930","DOI":"10.1200\/JCO.2013.54.5228","article-title":"p16 Protein Expression and Human Papillomavirus Status As Prognostic Biomarkers of Nonoropharyngeal Head and Neck Squamous Cell Carcinoma","volume":"32","author":"Chung","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"da Mata, S., Ferreira, J., Nicol\u00e1s, I., Esteves, S., Esteves, G., L\u00e9rias, S., Silva, F., Saco, A., Cochicho, D., and Cunha, M. (2021). P16 and HPV Genotype Significance in HPV-Associated Cervical Cancer\u2014A Large Cohort of Two Tertiary Referral Centers. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052294"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.18632\/oncotarget.1523","article-title":"p16 in HPV-associated cancers","volume":"4","author":"Munger","year":"2013","journal-title":"Oncotarget"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.virusres.2009.06.008","article-title":"Oncogenic activities of human papillomaviruses","volume":"143","year":"2009","journal-title":"Virus Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1042\/CS20050369","article-title":"Molecular biology of human papillomavirus infection and cervical cancer","volume":"110","author":"Doorbar","year":"2006","journal-title":"Clin. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"F55","DOI":"10.1016\/j.vaccine.2012.06.083","article-title":"The biology and life-cycle of human papillomaviruses","volume":"30","author":"Doorbar","year":"2012","journal-title":"Vaccine"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Schichl, K., and Doorbar, J. (2025). Regulation and Deregulation of Viral Gene Expression During High-Risk HPV Infection. Viruses, 17.","DOI":"10.3390\/v17070937"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Harwood, M.C., Dupzyk, A.J., Inoue, T., DiMaio, D., and Tsai, B. (2020). p120 catenin recruits HPV to \u03b3-secretase to promote virus infection. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008946"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e391","DOI":"10.4317\/jced.61057","article-title":"Expression of p12catenin in oral squamous cell carcinoma and apparently normal mucosa adjacent to oral squamous cell carcinoma","volume":"16","author":"Rajeev","year":"2024","journal-title":"J. Clin. Exp. Dent."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1136\/jclinpath-2011-200516","article-title":"Phosphorylated p120-catenin expression has predictive value for oral cancer progression","volume":"65","author":"Ma","year":"2012","journal-title":"J. Clin. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbamcr.2006.10.004","article-title":"Taking stock: The many surprising lives of p120-catenins","volume":"1773","author":"Yap","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Cell Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.ccr.2011.02.007","article-title":"Deletion of p120-Catenin Results in a Tumor Microenvironment with Inflammation and Cancer that Establishes It as a Tumor Suppressor Gene","volume":"19","author":"Stairs","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s00428-014-1630-6","article-title":"Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different","volume":"465","author":"Krupar","year":"2014","journal-title":"Virchows Arch."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e00915-19","DOI":"10.1128\/JVI.00915-19","article-title":"Tissue-Specific Gene Expression during Productive Human Papillomavirus 16 Infection of Cervical, Foreskin, and Tonsil Epithelium","volume":"93","author":"Chatterjee","year":"2019","journal-title":"J. Virol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.virol.2016.09.004","article-title":"Comparison of human papillomavirus type 16 replication in tonsil and foreskin epithelia","volume":"499","author":"Israr","year":"2016","journal-title":"Virology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3851\/IMP1512","article-title":"Effect of the HIV protease inhibitor amprenavir on the growth and differentiation of primary gingival epithelium","volume":"15","author":"Israr","year":"2010","journal-title":"Antivir. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1468-1293.2010.00863.x","article-title":"The HIV protease inhibitor lopinavir\/ritonavir (Kaletra) alters the growth, differentiation and proliferation of primary gingival epithelium","volume":"12","author":"Israr","year":"2010","journal-title":"HIV Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1111\/hiv.12100","article-title":"HIV nucleoside reverse transcriptase inhibitors efavirenz and tenofovir change the growth and differentiation of primary gingival epithelium","volume":"15","author":"Mitchell","year":"2013","journal-title":"HIV Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e01261-18","DOI":"10.1128\/JVI.01261-18","article-title":"Effect of Productive Human Papillomavirus 16 Infection on Global Gene Expression in Cervical Epithelium","volume":"92","author":"Kang","year":"2018","journal-title":"J. Virol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/BF00132885","article-title":"Organotypic (raft) epithelial tissue culture system for the differentiation-dependent replication of papillomavirus","volume":"18","author":"Meyers","year":"1996","journal-title":"Methods Cell Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1099\/0022-1317-83-11-2753","article-title":"Infectious human papillomavirus type 31b: Purification and infection of an immortalized human keratinocyte cell line","volume":"83","author":"Ozbun","year":"2002","journal-title":"J. Gen. Virol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"11291","DOI":"10.1128\/JVI.76.22.11291-11300.2002","article-title":"Human Papillomavirus Type 31b Infection of Human Keratinocytes and the Onset of Early Transcription","volume":"76","author":"Ozbun","year":"2002","journal-title":"J. Virol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.virusres.2009.10.019","article-title":"Inducible heat shock protein 70 enhances HPV31 viral genome replication and virion production during the differentiation-dependent life cycle in human keratinocytes","volume":"147","author":"Song","year":"2010","journal-title":"Virus Res."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Jackson, R., Rajadhyaksha, E.V., Loeffler, R.S., Flores, C.E., and Van Doorslaer, K. (2023). Characterization of 3D organotypic epithelial tissues reveals tonsil-specific differences in tonic interferon signaling. PLoS ONE, 18.","DOI":"10.1101\/2023.01.19.524743"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.virol.2004.02.011","article-title":"Propagation, infection, and neutralization of authentic HPV16 virus","volume":"322","author":"Christensen","year":"2004","journal-title":"Virology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e01216-18","DOI":"10.1128\/JVI.01216-18","article-title":"Inhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized Keratinocytes","volume":"93","author":"Guidry","year":"2019","journal-title":"J. Virol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"7381","DOI":"10.1128\/jvi.71.10.7381-7386.1997","article-title":"Synthesis of infectious human papillomavirus type 18 in differentiating epithelium transfected with viral DNA","volume":"71","author":"Meyers","year":"1997","journal-title":"J. Virol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/s41571-022-00603-7","article-title":"HPV-associated oropharyngeal cancer: Epidemiology, molecular biology and clinical management","volume":"19","author":"Lechner","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"001540","DOI":"10.1099\/jgv.0.001540","article-title":"The human papillomavirus oncoproteins: A review of the host pathways targeted on the road to transformation","volume":"102","author":"Scarth","year":"2021","journal-title":"J. Gen. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.semradonc.2021.02.006","article-title":"Biology of HPV Mediated Carcinogenesis and Tumor Progression","volume":"31","author":"Cosper","year":"2021","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.tim.2010.10.002","article-title":"Persistence of human papillomavirus infection: Keys to malignant progression","volume":"19","author":"Bodily","year":"2011","journal-title":"Trends Microbiol."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"McBride, A.A., and Warburton, A. (2017). The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006211"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Rossi, N.M., Dai, J., Xie, Y., Lou, H., Boland, J.F., Yeager, M., Orozco, R., Alvirez, E., Mirabello, L., and Gharzouzi, E. (2021). Extrachromosomal Amplification of Human Papillomavirus Episomes as a Mechanism of Cervical Carcinogenesis. bioRxiv, bioRxiv:2021.10.22.465367.","DOI":"10.1101\/2021.10.22.465367"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Schrank, T.P., Kim, S., Rehmani, H., Kothari, A., Wu, D., Yarbrough, W.G., and Issaeva, N. (2022). Direct Comparison of HPV16 Viral Genomic Integration, Copy Loss, and Structural Variants in Oropharyngeal and Uterine Cervical Cancers Reveal Distinct Relationships to E2 Disruption and Somatic Alteration. Cancers, 14.","DOI":"10.3390\/cancers14184488"},{"key":"ref_91","first-page":"134","article-title":"Understanding the HPV integration and its progression to cervical cancer","volume":"61","year":"2018","journal-title":"Infect. Genet. Evol. J. Mol. Epidemiol. Evol. Genet. Infect. Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41417-023-00682-3","article-title":"HPV E6\/E7: Insights into their regulatory role and mechanism in signaling pathways in HPV-associated tumor","volume":"31","author":"Peng","year":"2024","journal-title":"Cancer Gene Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1128\/jvi.65.2.606-612.1991","article-title":"Analysis of the physical state of different human papillomavirus DNAs in intraepithelial and invasive cervical neoplasm","volume":"65","author":"Cullen","year":"1991","journal-title":"J. Virol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1128\/jvi.69.5.2989-2997.1995","article-title":"Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells","volume":"69","author":"Jeon","year":"1995","journal-title":"J. Virol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"White, E.A. (2019). Manipulation of Epithelial Differentiation by HPV Oncoproteins. Viruses, 11.","DOI":"10.3390\/v11040369"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e31061","DOI":"10.1016\/j.heliyon.2024.e31061","article-title":"Oral and periodontal manifestation related during human papilloma virus infections: Update on early prognostic factors","volume":"10","author":"Amato","year":"2024","journal-title":"Heliyon"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1111\/j.1468-1293.2011.00973.x","article-title":"Effect of the HIV nucleoside reverse transcriptase inhibitor zidovudine on the growth and differentiation of primary gingival epithelium","volume":"13","author":"Mitchell","year":"2012","journal-title":"HIV Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1006\/viro.1998.9262","article-title":"Temporal and Spatial Expression of the E5a Protein during the Differentiation-Dependent Life Cycle of Human Papillomavirus Type 31b","volume":"248","author":"Mayer","year":"1998","journal-title":"Virology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/0022-2836(81)90460-5","article-title":"Diversity of cytokeratins","volume":"153","author":"Franke","year":"1981","journal-title":"J. Mol. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0092-8674(82)90400-7","article-title":"The catalog of human cytokeratins: Patterns of expression in normal epithelia, tumors and cultured cells","volume":"31","author":"Moll","year":"1982","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1046\/j.1365-2559.2002.01387.x","article-title":"Keratin expression in human tissues and neoplasms","volume":"40","author":"Chu","year":"2002","journal-title":"Histopathology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/BF01457542","article-title":"Changes in cytokeratin expression in epidermal keratinocytes during wound healing","volume":"103","author":"Watanabe","year":"1995","journal-title":"Histochem. Cell Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1368-8375(00)00094-4","article-title":"Gene expression of differentiation-specific keratins in oral epithelial dysplasia and squamous cell carcinoma","volume":"37","author":"Bloor","year":"2001","journal-title":"Oral Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/j.1432-0436.1985.tb00524.x","article-title":"Different patterns of cytokeratin expression in the normal epithelia of the upper respiratory tract","volume":"30","author":"Nagle","year":"1985","journal-title":"Differentiation"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.3892\/ol.2014.2591","article-title":"Keratin 5 expression in squamocellular carcinoma of the head and neck","volume":"8","author":"Vasca","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1600-0714.2007.00609.x","article-title":"An altered keratinocyte phenotype in oral submucous fibrosis: Correlation of keratin K17 expression with disease severity","volume":"37","author":"Lalli","year":"2008","journal-title":"J. Oral Pathol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"100394","DOI":"10.1016\/j.oor.2024.100394","article-title":"Combined spatial Keratin expression profiles at the invasive front represent a prognostic classifier for head and neck cancer","volume":"10","author":"Haughton","year":"2024","journal-title":"Oral Oncol. Rep."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Na\u0142\u0119cz, D., \u015awi\u0119tek, A., Hudy, D., Wiczkowski, K., Z\u0142otopolska, Z., and Strzelczyk, J.K. (2024). Assessment of Concentration KRT6 Proteins in Tumor and Matching Surgical Margin from Patients with Head and Neck Squamous Cell Carcinoma. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137356"},{"key":"ref_109","first-page":"1","article-title":"Differentiation and Tumor Progression","volume":"Volume 139","author":"Fusenig","year":"1995","journal-title":"Skin Cancer: Basic Science, Clinical Research and Treatment"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Matthias, C., Mack, B., Berghaus, A., and Gires, O. (2008). Keratin 8 expression in head and neck epithelia. BMC Cancer, 8.","DOI":"10.1186\/1471-2407-8-267"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"(2020). Expression of Cytokeratin 8 in oral squamous cell cancer. Indian J. Pathol. Oncol., 5, 55\u201360.","DOI":"10.18231\/2394-6792.2018.0011"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"528","DOI":"10.3892\/ol.2021.12789","article-title":"Human papillomavirus-16 infection and p16 expression in oral squamous cell carcinoma","volume":"22","author":"Tokuzen","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1097\/PAI.0000000000001124","article-title":"Expression of Human Papillomavirus and the p16 Gene in Oral Potentially Malignant Disorders (OPMD): A Comparative Study With Oral Squamous Cell Carcinoma","volume":"31","author":"Baddevithana","year":"2023","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"11270","DOI":"10.1038\/s41598-025-95643-1","article-title":"Correlation and prognosis analysis of human papillomavirus infection and P16 expression in oral and oropharyngeal squamous cell carcinomas","volume":"15","author":"Lin","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1200\/JCO.2004.00.3335","article-title":"Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis","volume":"24","author":"Weinberger","year":"2006","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/683\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:58:17Z","timestamp":1771495097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/4\/683"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,19]]},"references-count":115,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cancers18040683"],"URL":"https:\/\/doi.org\/10.3390\/cancers18040683","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,19]]}}}