Herber R, Liem A, Pitot H, Lambert P F
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison 53706, USA.
J Virol. 1996 Mar;70(3):1873-81. doi: 10.1128/JVI.70.3.1873-1881.1996.
The human papillomavirus type 16 (HPV-16) genome is commonly present in human cervical carcinoma, in which a subset of the viral genes, E6 and E7, are expressed. The HPV-16 E6 and E7 gene products can associated with and inactivate the tumor suppressor proteins p53 and Rb (the retinoblastoma susceptibility gene product), and in tissue culture cells, these viral genes display oncogenic properties. These findings have led to the hypothesis that E6 and E7 contribute to cervical carcinogenesis. This hypothesis has recently been tested by using transgenic mice as an animal model. HPV-16 E6 and E7 together were found to induce cancers in multiple tissues in which they were expressed, including squamous cell carcinoma, the cancer type most commonly associated with HPV-16 in the human cervix. We have extended these studies to investigate the in vivo activities of HPV-16 E7 when expressed in squamous epithelia of transgenic mice. Grossly, E7 transgenic mice had multiple phenotypes, including wrinkled skin that was apparent prior to the appearance of hair on neonates, thickened ears, and loss of hair in adults. In lines of mice expressing higher levels of E7, we observed stunted growth and mortality at an early age, potentially caused by an incapacity to feed. Histological analysis demonstrated that E7 causes epidermal hyperplasia in multiple transgenic lineages with high penetrance. This epithelial hyperplasia was characterized by an expansion of the proliferating compartment and an expansion of the keratin 10-positive layer of cells and was associated with hyperkeratosis. Hyperplasia was found at multiple sites in the animals in addition to the skin, including the mouth palate, esophagus, forestomach, and exocervix. In multiple transgenic lineages, adult animals developed skin tumors late in life with low penetrance. These tumors arose from the squamous epithelia and from sebaceous glands and were characterized histologically to be highly differentiated, locally invasive, and aggressive in their growth properties. On the basis of these phenotypes, we conclude that HPV-16 E7 can alter epithelial cell growth parameters sufficiently to potentiate tumorigenesis in mice.
人乳头瘤病毒16型（HPV - 16）基因组常见于人类宫颈癌中，在宫颈癌中病毒基因的一个子集E6和E7会表达。HPV - 16 E6和E7基因产物可与肿瘤抑制蛋白p53和Rb（视网膜母细胞瘤易感基因产物）结合并使其失活，在组织培养细胞中，这些病毒基因具有致癌特性。这些发现导致了一种假说，即E6和E7促成了宫颈癌的发生。最近通过使用转基因小鼠作为动物模型对这一假说进行了验证。发现HPV - 16 E6和E7共同在其表达的多个组织中诱发癌症，包括鳞状细胞癌，这是人类宫颈中最常与HPV - 16相关的癌症类型。我们扩展了这些研究，以调查HPV - 16 E7在转基因小鼠鳞状上皮中表达时的体内活性。大体上，E7转基因小鼠有多种表型，包括在新生小鼠毛发出现之前就明显可见的皮肤褶皱、耳朵增厚以及成年小鼠掉毛。在表达较高水平E7的小鼠品系中，我们观察到早期生长发育迟缓以及死亡，这可能是由于无法进食所致。组织学分析表明，E7在多个转基因谱系中以高 penetrance 导致表皮增生。这种上皮增生的特征是增殖区室扩大以及角蛋白10阳性细胞层扩大，并伴有角化过度。除了皮肤外，在动物的多个部位包括口腔上颚、食道、前胃和子宫颈外口都发现了增生。在多个转基因谱系中，成年动物在生命后期发生皮肤肿瘤，penetrance 较低。这些肿瘤起源于鳞状上皮和皮脂腺，组织学特征为高度分化、局部侵袭性且生长特性具有侵袭性。基于这些表型，我们得出结论，HPV - 16 E7能够充分改变上皮细胞生长参数，从而增强小鼠的肿瘤发生。
