Persistence of high-grade cervical dysplasia and cervical cancer requires the continuous expression of the human papillomavirus type 16 E7 oncogene.
Several mucosotropic human papillomaviruses (HPV), including HPV type 16 (HPV-16), are etiologic agents of a subset of anogenital cancers and head and neck squamous cell carcinomas. In mice, HPV-16 E7 is the most potent of the papillomaviral oncogenes in the development of cervical disease. Furthermore, interfering specifically with the expression of E7 in HPV-positive cell lines derived from human cervical cancers inhibits their ability to proliferate, indicating that the expression of E7 is important in maintaining the transformed phenotype in vitro. To assess the temporal role of E7 in maintaining HPV-associated tumors and precancerous lesions in vivo, we generated Bi-L E7 transgenic mice that harbor a tetracycline-inducible transgene that expresses both HPV-16 E7 and firefly luciferase. When we crossed Bi-L E7 mice to a K5-tTA transgene-inducing line of mice, which expresses a tetracycline-responsive transactivator selectively in the stratified squamous epithelia, the resulting Bi-L E7/K5-tTA bitransgenic mice expressed E7 and luciferase in the skin and cervical epithelium, and doxycycline repressed this expression. Bitransgenic mice displayed several overt and acute epithelial phenotypes previously shown to be associated with the expression of E7, and these phenotypes were reversed on treatment with doxycycline. Repressing the expression of E7 caused the regression of high-grade cervical dysplasia and established cervical tumors, indicating that they depend on the continuous expression of E7 for their persistence. These results suggest that E7 is a relevant target not only for anticancer therapy but also for the treatment of HPV-positive dysplastic cervical lesions.
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Sean F
SF
Jabbar
Linda
L
Abrams
Adam
A
Glick
Paul F
PF
Lambert
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000821:virology; D002584:Cervix Uteri / Q000187:drug effects / Q000473:pathology; D017931:DNA Primers; D004261:DNA Replication / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D048888:Fireflies / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000821:virology; D052162:Human papillomavirus 16; D006801:Humans; D008156:Luciferases / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000187:drug effects / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D016133:Polymerase Chain Reaction; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000821:virology*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology*
D017931:DNA Primers; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D008156:Luciferases; D004318:Doxycycline