The role of the human papillomavirus type 16 E7 oncoprotein in the maintenance of cervical cancer.

摘要

High-risk mucosotropic human papillomaviruses (HPV), including HPV-16, are associated etiologically with nearly all cervical cancers and a subset of head and neck squamous cell carcinomas (HNSCC). We previously generated K14E6 and K14E7 transgenic mice, which express the HPV-16 E6 and E7 oncoproteins in the stratified squamous epithelia, to characterize their oncogenic properties in vivo and showed that E7 is the dominant oncogene in cervical carcinogenesis. Studies using HPV-positive cell lines derived from human cervical cancers have indicated the importance of the continuous expression of E7 for maintaining their transformed phenotypes in vitro; however, whether this is predictive of the in vivo dependence of HPV-associated cancers on E7 remains unclear.;To determine whether the continuous expression of HPV-16 E7 is required for the persistence of neoplastic cervical disease in vivo, I have generated Bi-L E7 transgenic mice that harbor a construct containing a bi-directional tetracycline operator flanked by HPV-16 E7 in one direction and firefly luciferase in the other. Crossing Bi-L E7 mice to transgene-inducing lines of mice that express the tetracycline transactivator protein in the stratified squamous epithelia yielded bi-transgenic mice in which I could repress the expression of luciferase and E7 by administering doxycycline. The cervical cancers and high-grade dysplasias that arose in bi-transgenic mice treated chronically with estrogen regressed when I repressed the expression of E7, even when the E6 oncoprotein was co-expressed constitutively, indicating that they require E7 for their persistence. Interestingly, however, in the context of lengthening the duration and reducing the level of expression of E7, some cervical cancers arose even after I silenced E7.;In addition, I continued work initiated by a former member of our laboratory, Katerina Strati, who treated K14E6, K14E7, and K14E6/K14E7 mice with the chemical carcinogen 4-nitroquinoline-1-oxide (4-NQO) to show that E7 is the dominant oncogene in HNSCC. By halving the duration of treatment with 4-NQO, I found that E6 synergizes with E7 to contribute to HNSCC. Surprisingly, its capacity to do so was independent of its ability to bind to either of two families of proteins previously shown to be important for its oncogenicity in the skin and cervix.