PROGRESSIVE SQUAMOUS EPITHELIAL NEOPLASIA IN K14-HUMAN PAPILLOMAVIRUS TYPE-16 TRANSGENIC MICE
PROGRESSIVE SQUAMOUS EPITHELIAL NEOPLASIA IN K14-HUMAN PAPILLOMAVIRUS TYPE-16 TRANSGENIC MICE
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DOI：
10.1128/jvi.68.7.4358-4368.1994
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发表时间：
1994-07-01
影响因子：
5.4
通讯作者：
HANAHAN, D
中科院分区：
文献类型：
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作者：
ARBEIT, JM;MUNGER, K;HANAHAN, D
为了模拟人乳头瘤病毒诱导的肿瘤进展，使用人角蛋白 14 (K14) 增强子/启动子将人乳头瘤病毒 16 型 (HPV16) 早期区域的表达靶向转基因小鼠的鳞状上皮基底细胞。产生了 21 只转基因创始小鼠，并建立了 8 个携带野生型或突变型 HPV16 早期区域（不表达 E1 或 E2 基因）的品系。正如人类癌症的特征一样，E6 和 E7 基因在这些突变体中保持完整。 E1或E2功能的缺失并不影响转基因小鼠最终形成的表型的严重程度。多个表皮和鳞状粘膜部位出现增生、乳头状瘤病和发育不良，包括耳和躯干皮肤、面部、口鼻部和眼睑以及肛门。耳朵是受影响最明显的部位，所有系中均存在病理，外显率达 100%。这种表型也经历了明显的阶段。最初是轻度增生，随后是增生，进一步发展为不典型增生和乳头状瘤病。在组织病理学进展过程中，通过 5-溴-2'-脱氧尿苷掺入确定细胞 DNA 合成逐渐增加，并且通过 K5、K14、K10 和聚丝蛋白的免疫组织化学显示角质形成细胞终末分化发生严重扰动。这些 K14-HPV16 转基因小鼠为研究 HPV16 癌基因在鳞状上皮肿瘤进展中的作用提供了机会，并提供了一个模型来识别致癌所需的遗传和表观遗传因素。
To model human papillomavirus-induced neoplastic progression, expression of the early region of human papillomavirus type 16 (HPV16) was targeted to the basal cells of the squamous epithelium in transgenic mice, using a human keratin 14 (K14) enhancer/promoter. Twenty-one transgenic founder mice were produced, and eight lines carrying either wild-type or mutant HPV16 early regions that did not express the E1 or E2 genes were established. As is characteristic of human cancers, the E6 and E7 genes remained intact in these mutants. The absence of E1 or E2 function did not influence the severity of the phenotype that eventually developed in the transgenic mice. Hyperplasia, papillomatosis, and dysplasia appeared at multiple epidermal and squamous mucosal sites, including ear and truncal skin, face, snout and eyelids, and anus. The ears were the most consistently affected site, with pathology being present in all lines with 100% penetrance. This phenotype also progressed through discernible stages. An initial mild hyperplasia was followed by hyperplasia, which further progressed to dysplasia and papillomatosis. During histopathological progression, there was an incremental increase in cellular DNA synthesis, determined by 5-bromo-2'-deoxyuridine incorporation, and a profound perturbation in keratinocyte terminal differentiation, as revealed by immunohistochemistry to K5, K14, and K10 and filaggrin. These K14-HPV16 transgenic mice present an opportunity to study the role of the HPV16 oncogenes in the neoplastic progression of squamous epithelium and provide a model with which to identify genetic and epigenetic factors necessary for carcinogenesis.