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Due to their low frequency, the molecular mechanisms responsible for their aggressiveness are poorly understood. In this work we studied the role of the phosphatase DUSP1, a negative regulator of MAPK activity, in controlling SG-SCC progression. We generated <jats:italic>DUSP1<\/jats:italic> KO clones in A253 human cells. These clones showed a reduced ability to grow in 2D, self-renew in ECM matrices and to form tumors in immunodeficient mice. This was caused by an overactivation of the stress and apoptosis kinase JNK1\/2 in <jats:italic>DUSP1<\/jats:italic><jats:sup>\u2212\/+<\/jats:sup> clones. Interestingly, RNAseq analysis revealed that the expression of SOX2, a well-known self-renewal gene was decreased at the mRNA and protein levels in <jats:italic>DUSP1<\/jats:italic><jats:sup>\u2212\/+<\/jats:sup> cells. Unexpectedly, CRISPR-KO of <jats:italic>SOX2<\/jats:italic> did not recapitulate <jats:italic>DUSP1<\/jats:italic><jats:sup>\u2212\/+<\/jats:sup> phenotype, and <jats:italic>SOX2<\/jats:italic>-null cells had an enhanced ability to self-renew and to form tumors in mice. Gene expression analysis demonstrated that <jats:italic>SOX2<\/jats:italic>-null cells have a decreased squamous differentiation profile -losing TP63 expression- and an increased migratory phenotype, with an enhanced epithelial to mesenchymal transition signature. In summary, our data indicates that DUSP1 and SOX2 have opposite functions in SG-SCC, being DUSP1 necessary for tumor growth and SOX2 dispensable showing a tumor suppressor function. Our data suggest that the combined expression of SOX2 and DUSP1 could be a useful biomarker to predict progression in patients with SG-SCCs.<\/jats:p>","DOI":"10.1038\/s41598-024-65945-x","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T20:32:09Z","timestamp":1719865929000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["DUSP1 and SOX2 expression determine squamous cell carcinoma of the salivary gland progression"],"prefix":"10.1038","volume":"14","author":[{"given":"Luc\u00eda","family":"Acero-Riaguas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Bel\u00e9n","family":"Griso-Acevedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"SanLorenzo-Vaquero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Ib\u00e1\u00f1ez-Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Mar\u00eda","family":"Fernandez-Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9677-921X","authenticated-orcid":false,"given":"Marta","family":"Mascaraque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"S\u00e1nchez-Siles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iv\u00e1n","family":"L\u00f3pez-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Ben\u00edtez-Buelga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Ruiz","family":"Bravo-Burguillos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Castelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Luis","family":"Cebri\u00e1n-Carretero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Perona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro","family":"Sastre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Sastre-Perona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,1]]},"reference":[{"key":"65945_CR1","doi-asserted-by":"publisher","first-page":"597","DOI":"10.3322\/caac.21807","volume":"73","author":"CE Steuer","year":"2023","unstructured":"Steuer, C. 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