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We studied the distribution of oral and pharyngeal lesions in HPV16\u2010transgenic mice where the expression of all the HPV16 early genes is targeted to keratinising squamous epithelia by the cytokeratin 14 (<jats:italic>Krt14<\/jats:italic>) gene promoter. At 30 weeks of age, 100% of mice developed low\u2010 and high\u2010grade intraepithelial dysplasia at multiple sites. Twenty per cent of animals developed invasive cancers that remarkably were restricted to the tongue base, in association with the circumvallate papilla. The lesions maintained expression of CK14 (KRT14) and the HPV16 <jats:italic>E6<\/jats:italic> and <jats:italic>E7<\/jats:italic> oncogenes, and displayed deregulated cell proliferation and up\u2010regulation of p16<jats:sup>INK4A<\/jats:sup>. Malignant lesions were poorly differentiated and destroyed the tongue musculature. We hypothesised that the tongue base area might contain a transformation zone similar to those observed in the cervix and anus, explaining why HPV\u2010positive cancers target that area specifically. Immunohistochemistry for two transformation zone markers, CK7 (KRT7) and p63 (TP63), revealed a squamocolumnar junction in the terminal duct of von Ebner's gland, composed of CK7<jats:sup>+<\/jats:sup> luminal cells and p63<jats:sup>+<\/jats:sup> basal cells. Dysplastic and invasive lesions retained diffuse p63 expression but only scattered positivity for CK7. Site\u2010specific HPV\u2010induced carcinogenesis in the tongue base may be explained by the presence of a transformation zone in the circumvallate papilla. This mouse model reproduces key morphological and molecular features of HPV\u2010positive HNSCC, providing a unique <jats:italic>in vivo<\/jats:italic> tool for basic and translational research. \u00a9 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5387","type":"journal-article","created":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T02:45:42Z","timestamp":1580265942000},"page":"4-11","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice"],"prefix":"10.1002","volume":"251","author":[{"given":"Ver\u00f3nica F","family":"Mestre","sequence":"first","affiliation":[{"name":"CITAB, Universidade de Tr\u00e1s\u2010os\u2010Montes e Alto Douro, UTAD  Vila Real Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Medeiros\u2010Fonseca","sequence":"additional","affiliation":[{"name":"CITAB, Universidade de Tr\u00e1s\u2010os\u2010Montes e Alto Douro, UTAD  Vila Real 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