{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:55:10Z","timestamp":1793836510334,"version":"4.6.1"},"reference-count":47,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T00:00:00Z","timestamp":1755993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2022\/08908-0"],"award-info":[{"award-number":["2022\/08908-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2022\/00994-5"],"award-info":[{"award-number":["2022\/00994-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cisplatin resistance remains a major therapeutic challenge in oral squamous cell carcinoma (OSCC), leading to treatment failure and poor outcomes. This study aimed to generate and characterize cisplatin-resistant OSCC models to elucidate resistance mechanisms. Two resistant OSCC cell lines (SCC-9R and HSC-3R) were developed through gradual dose escalation. Parental and resistant cells were analyzed via RNA-seq and gene set enrichment analysis, and validated through RT-qPCR, Western blot, immunofluorescence, and gelatin zymography. Functional assays, including 2D and 3D migration and invasion models, assessed phenotypic changes. A multi-omics analysis revealed molecular alterations in resistant cells, including 305 differentially expressed genes (DEGs) in HSC-3R (187 upregulated) and 782 in SCC-9R (298 upregulated) versus parental lines, with enrichment for extracellular matrix organization (p &lt; 0.001) and consistent epithelial\u2013mesenchymal transition (EMT) activation (p &lt; 0.001), demonstrated by the upregulation of ZEB1, ZEB2, Vimentin, and TWIST1, and E-cadherin suppression. Functional validation confirmed an aggressive phenotype, including increased migration (p &lt; 0.05), invasion (p &lt; 0.01), and elevated MMP-2 (p &lt; 0.01) and MMP-9 (p &lt; 0.001) activity. Findings were verified in 3D spheroid models. Overall, cisplatin resistance in OSCC involves EMT, inflammatory signaling, and metabolic adaptation. The consistency of these features across both models supports the robustness of this in vitro system and reveals targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/cells14171311","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:09:32Z","timestamp":1756080572000},"page":"1311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Generation and Characterization of Cisplatin-Resistant Oral Squamous Cell Carcinoma Cells Displaying an Epithelial\u2013Mesenchymal Transition Signature"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2173-7672","authenticated-orcid":false,"given":"Everton Freitas","family":"de Morais","sequence":"first","affiliation":[{"name":"Graduate Program in Oral Biology, School of Dentistry, University of Campinas, Piracicaba 13414-018, SP, Brazil"},{"name":"Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba 13414-018, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilianny Querino Rocha","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Graduate Program in Oral Biology, School of Dentistry, University of Campinas, Piracicaba 13414-018, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cintia Eliza","family":"Marques","sequence":"additional","affiliation":[{"name":"Graduate Program in Oral Biology, School of Dentistry, University of Campinas, Piracicaba 13414-018, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F\u00e1bio Haach","family":"T\u00e9o","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba 13414-018, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisele Vieira","family":"Rocha","sequence":"additional","affiliation":[{"name":"Gon\u00e7alo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ\/BA), Salvador 40296-710, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila Oliveira","family":"Rodini","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Bauru School of Dentistry, University of S\u00e3o Paulo, Bauru 05508-220, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8922-2985","authenticated-orcid":false,"given":"Clarissa A.","family":"Gurgel","sequence":"additional","affiliation":[{"name":"Gon\u00e7alo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ\/BA), Salvador 40296-710, BA, Brazil"},{"name":"Department of Propaedeutics, School of Dentistry, Federal University of Bahia, Salvador 40110-909, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuula","family":"Salo","sequence":"additional","affiliation":[{"name":"Cancer and Translational Medicine Research Unit, Faculty of Medicine and Medical Research Center Oulu, Oulu University Hospital, University of Oulu, 90014 Oulu, Finland"},{"name":"Department of Pathology, Helsinki University Hospital, Institute of Oral and Maxillofacial Disease, University of Helsinki, and HUSLAB, 00029 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgard","family":"Graner","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba 13414-018, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5285-3046","authenticated-orcid":false,"given":"Ricardo D.","family":"Coletta","sequence":"additional","affiliation":[{"name":"Graduate Program in Oral Biology, School of Dentistry, University of Campinas, Piracicaba 13414-018, SP, Brazil"},{"name":"Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba 13414-018, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Coletta, R.D., Yeudall, W.A., and Salo, T. 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