{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:49:31Z","timestamp":1792097371586,"version":"4.4.0"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universidade De S\u00e3o Paulo","id":[{"id":"https:\/\/ror.org\/036rp1748","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Med Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent cutaneous \u03b2-human papillomavirus infection and increased risk of cutaneous squamous cell carcinoma (cSCC). The cyclic GMP-AMP synthase (cGAS)\u2013stimulator of interferon genes (STING) pathway links cytosolic DNA sensing, genomic instability and innate immune activation, but its expression in EV-associated cSCC remains poorly defined. We quantified STING, p53 and BCL2 immunohistochemical expression in tissue microarrays containing 47 EV-associated and 83 non-EV cSCCs. Tumor H-scores were medians across valid cores; primary comparisons used patient-clustered generalized estimating equations (GEE). STING expression was higher in EV-associated tumors (median H-score 192.4 vs. 149.5); in grade-adjusted GEE, EV status was associated with a\u2009+\u200937.2-unit difference (95% confidence interval [CI] 23.4\u201351.0;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). The EV\u2013non-EV STING difference varied by histological grade (interaction\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0067), with the largest estimated difference in grade 1 tumors. p53 expression was also higher in EV tumors (97.7 vs. 36.3; adjusted difference\u2009+\u200943.8, 95% CI 18.8\u201368.8;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), and EV tumors had higher odds of belonging to a higher p53 tertile (odds ratio [OR] 3.54, 95% CI 1.98\u20136.32;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). BCL2 remained low and was not significantly associated with EV (adjusted difference\u2009\u2212\u20091.93, 95% CI\u2009\u2212\u20094.84 to 0.98;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.193). STING and p53 remained positively associated after adjustment for histological grade, EV status and patient clustering. These findings define an altered STING protein-expression phenotype in EV-associated cSCC, accompanied by increased p53 expression but no independent BCL2 association, and support functional investigation of cGAS\u2013STING signaling.\n                  <\/jats:p>","DOI":"10.1007\/s12032-026-03417-0","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:50:20Z","timestamp":1789451420000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential STING and p53 expression in epidermodysplasia verruciformis-associated versus non-EV cutaneous squamous cell carcinomas"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1140-3046","authenticated-orcid":false,"given":"Luis Alberto Ribeiro","family":"Fr\u00f3es","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1539-7069","authenticated-orcid":false,"given":"Walmar Roncalli Pereira","family":"de Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3385-0293","authenticated-orcid":false,"given":"Paulo","family":"Stahlschmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1296-2541","authenticated-orcid":false,"given":"Lana Luiza","family":"da Cruz Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4157-8127","authenticated-orcid":false,"given":"Naiura Vieira","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6380-7192","authenticated-orcid":false,"given":"Mirian Nacagami","family":"Sotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"issue":"4","key":"3417_CR1","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/ng1044","volume":"32","author":"N Ramoz","year":"2002","unstructured":"Ramoz N, Rueda LA, Bouadjar B, Montoya LS, Orth G, Favre M. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet. 2002;32(4):579\u201381. https:\/\/doi.org\/10.1038\/ng1044.","journal-title":"Nat Genet"},{"issue":"9","key":"3417_CR2","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.1084\/jem.20170308","volume":"215","author":"SJ de Jong","year":"2018","unstructured":"de Jong SJ, Cr\u00e9quer A, Matos I, Hum D, Gunasekharan V, Lorenzo L, Jabot-Hanin F, Imahorn E, Arias AA, Vahidnezhad H, Youssefian L, Markle JG, Patin E, D\u2019Amico A, Wang CQF, Full F, Ensser A, Leisner TM, Parise LV, Bouaziz M, Maya NP, Cadena XR, Saka B, Saeidian AH, Aghazadeh N, Zeinali S, Itin P, Krueger JG, Laimins L, Abel L, Fuchs E, Uitto J, Franco JL, Burger B, Orth G, Jouanguy E, Casanova J-L. The human CIB1\u2013EVER1\u2013EVER2 complex governs keratinocyte-intrinsic immunity to \u03b2-papillomaviruses. 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Nature. 2017;548(7668):461\u20135. https:\/\/doi.org\/10.1038\/nature23449.","journal-title":"Nature"},{"issue":"7","key":"3417_CR5","doi-asserted-by":"publisher","first-page":"e1010725","DOI":"10.1371\/journal.ppat.1010725","volume":"18","author":"E Gusho","year":"2022","unstructured":"Gusho E, Laimins LA. Human papillomaviruses sensitize cells to DNA damage induced apoptosis by targeting the innate immune sensor cGAS. PLoS Pathog. 2022;18(7):e1010725. https:\/\/doi.org\/10.1371\/journal.ppat.1010725.","journal-title":"PLoS Pathog"},{"issue":"1","key":"3417_CR6","doi-asserted-by":"publisher","first-page":"3667","DOI":"10.1038\/s41467-018-06027-1","volume":"9","author":"GJ Inman","year":"2018","unstructured":"Inman GJ, Wang J, Nagano A, Alexandrov LB, Purdie KJ, Taylor RG, Sherwood V, Thomson J, Hogan S, Spender LC, South AP, Stratton M, Chelala C, Harwood CA, Proby CM, Leigh IM. 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Analysis of p53 and bcl-2 protein expression in the non-tumorigenic, pretumorigenic, and tumorigenic keratinocytic hyperproliferative lesions. J Cutan Pathol. 2004;31(10):643\u201351. https:\/\/doi.org\/10.1111\/j.0303-6987.2004.00244.x.","journal-title":"J Cutan Pathol"},{"issue":"21","key":"3417_CR9","doi-asserted-by":"publisher","first-page":"10408","DOI":"10.1128\/JVI.00902-08","volume":"82","author":"MP Underbrink","year":"2008","unstructured":"Underbrink MP, Howie HL, Bedard KM, Koop JI, Galloway DA. E6 proteins from multiple human betapapillomavirus types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation. 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Cutaneous human papillomavirus E6 impairs the cGAS-STING pathway. mSphere. 2026;11(3):e00859\u201325. https:\/\/doi.org\/10.1128\/msphere.00859-25.","journal-title":"mSphere"},{"issue":"13","key":"3417_CR15","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.3390\/cancers16132425","volume":"16","author":"A Menz","year":"2024","unstructured":"Menz A, Zerneke J, Viehweger F, B\u00fcy\u00fccek S, Dum D, Schlichter R, Hinsch A, Bawahab AA, Fraune C, Bernreuther C, Kluth M, Hube-Magg C, M\u00f6ller K, Lutz F, Reiswich V, Luebke AM, Lebok P, Weidemann SA, Sauter G, Lennartz M, Jacobsen F, Clauditz TS, Marx AH, Simon R, Steurer S, Burandt E, Gorbokon N, Minner S, Krech T. Stimulator of Interferon Genes Protein (STING) Expression in Cancer Cells: A Tissue Microarray Study Evaluating More than 18,000 Tumors from 139 Different Tumor Entities. Cancers (Basel). 2024;16(13):2425. https:\/\/doi.org\/10.3390\/cancers16132425.","journal-title":"Cancers (Basel)"},{"issue":"18","key":"3417_CR16","doi-asserted-by":"publisher","first-page":"4507","DOI":"10.3390\/cancers13184507","volume":"13","author":"M Piipponen","year":"2021","unstructured":"Piipponen M, Riihil\u00e4 P, Nissinen L, K\u00e4h\u00e4ri V-M. The role of p53 in progression of cutaneous squamous cell carcinoma. Cancers (Basel). 2021;13(18):4507. https:\/\/doi.org\/10.3390\/cancers13184507.","journal-title":"Cancers (Basel)"},{"key":"3417_CR17","doi-asserted-by":"publisher","first-page":"109552","DOI":"10.1016\/j.cellsig.2020.109552","volume":"69","author":"M Krze\u015bniak","year":"2020","unstructured":"Krze\u015bniak M, Zajkowicz A, Gdowicz-K\u0142osok A, G\u0142owala-Kosi\u0144ska M, \u0141asut-Szyszka B, Rusin M. Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity. Cell Signal. 2020;69:109552. https:\/\/doi.org\/10.1016\/j.cellsig.2020.109552.","journal-title":"Cell Signal"},{"issue":"4","key":"3417_CR18","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.ccell.2021.01.003","volume":"39","author":"M Ghosh","year":"2021","unstructured":"Ghosh M, Saha S, Bettke J, Nagar R, Parrales A, Iwakuma T, van der Velden AWM, Martinez LA. Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Cancer Cell. 2021;39(4):494\u2013e5085. https:\/\/doi.org\/10.1016\/j.ccell.2021.01.003.","journal-title":"Cancer Cell"},{"issue":"9","key":"3417_CR19","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1038\/ncb3586","volume":"19","author":"S Gl\u00fcck","year":"2017","unstructured":"Gl\u00fcck S, Guey B, Gulen MF, Wolter K, Kang T-W, Schmacke NA, Bridgeman A, Rehwinkel J, Zender L, Ablasser A. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol. 2017;19(9):1061\u201370. https:\/\/doi.org\/10.1038\/ncb3586.","journal-title":"Nat Cell Biol"}],"container-title":["Medical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-026-03417-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12032-026-03417-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-026-03417-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:41:27Z","timestamp":1792096887000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12032-026-03417-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":19,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["3417"],"URL":"https:\/\/doi.org\/10.1007\/s12032-026-03417-0","relation":{},"ISSN":["1559-131X"],"issn-type":[{"value":"1559-131X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]},"assertion":[{"value":"21 May 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The Institutional Ethics Committee of Hospital das Cl\u00ednicas, University of S\u00e3o Paulo, waived the requirement for informed consent due to the retrospective nature of the study and the exclusive use of archived, anonymized formalin-fixed, paraffin-embedded specimens.","order":2,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable. This study does not contain individually identifiable data, images, or videos of human participants.","order":3,"name":"Ethics","label":"Consent to publish","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. It was approved by the Institutional Ethics Committee of Hospital das Cl\u00ednicas, University of S\u00e3o Paulo (approval number #50871415.2.0000.0068).","order":4,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"286"}}