Head and neck squamous cell carcinomas (HNSCCs) associated with human papillomavirus (HPV) occur specifically in the tonsils and the tongue base, but the reasons for this specificity remain unknown. We studied the distribution of oral and pharyngeal lesions in HPV16-transgenic mice where the expression of all the HPV16 early genes is targeted to keratinising squamous epithelia by the cytokeratin 14 (Krt14) gene promoter. At 30 weeks of age, 100% of mice developed low- and high-grade 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 E6 and E7 oncogenes, and displayed deregulated cell proliferation and up-regulation of p16INK4A . 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-positive 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+ luminal cells and p63+ basal cells. Dysplastic and invasive lesions retained diffuse p63 expression but only scattered positivity for CK7. Site-specific HPV-induced 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-positive HNSCC, providing a unique in vivo tool for basic and translational research. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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HPV16足以在转基因小鼠的舌根中诱导鳞状细胞癌。

与人乳头瘤病毒（HPV）相关的头颈部鳞状细胞癌（HNSCC）专门发生在扁桃体和舌根中，但是这种特异性的原因仍然未知。我们研究了HPV16转基因小鼠中口腔和咽部病变的分布，其中所有HPV16早期基因的表达都通过细胞角蛋白14（Krt14）基因启动子靶向角化鳞状上皮细胞。在30周龄时，100％的小鼠在多个部位出现了低度和高度上皮内异型增生。20％的动物患上侵袭性癌症，与环周乳头相关，明显局限于舌根。病变保持CK14（KRT14）和HPV16 E6和E7癌基因的表达，并显示出细胞增殖失调和p16INK4A上调。恶性病变分化差，破坏了舌部肌肉组织。我们假设舌基区域可能包含一个类似于在子宫颈和肛门中观察到的转变区域，这解释了为什么HPV阳性癌症专门针对该区域。两种转化区标记CK7（KRT7）和p63（TP63）的免疫组织化学显示，在冯·埃伯纳腺的末端导管中有一个鳞状小柱交界处，由CK7 +腔细胞和p63 +基底细胞组成。异常增生性和浸润性病变保留了弥漫性p63表达，但CK7仅散在阳性。HPV诱导的舌根部位癌变可能是由周缘乳头中存在一个转化区来解释的。该小鼠模型再现了HPV阳性HNSCC的关键形态和分子特征，为基础和转化研究提供独特的体内工具。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版