Development of Skin Tumors in Mice Transgenic for Early Genes of Human Papillomavirus Type 8

Abstract

The cutaneous human papillomavirus (HPV) 8 is clearly involved in skin cancer development in epidermodysplasia verruciformis patients and its early genes E2, E6, and E7 have been implicated in cell transformation in vitro. To examine the functions of these genes in vivo we integrated the complete early region of HPV8 into the genome of DBA/Bl6 mice. To target their expression to the basal layer of the squamous epithelia the transgenes were put under the control of the keratin-14 promoter. Transgenic mice were back-crossed for up to six generations into both FVB/N and Bl6 mouse strains. Whereas none of the HPV8 transgene-negative littermates developed lesions in the skin or any other organ, 91% of HPV8-transgenic mice developed single or multifocal benign tumors, characterized by papillomatosis, acanthosis, hyperkeratosis, and varying degrees of epidermal dysplasia. Squamous cell carcinomas developed in 6% of the transgenic FVB/N mice. Real-time reverse transcription-PCR showed highest expression levels for HPV8-E2, followed by E7 and E6. There was no consistent difference in relative viral RNA levels between healthy or dysplastic skin and malignant skin tumors. Whereas UV-induced mutations in the tumor suppressor gene p53 are frequently detected in human skin carcinomas, mutations in p53 were not observed either in the benign or malignant mouse tumors. Nonmelanoma skin cancer developed in HPV8-transgenic mice without any treatment with physical or chemical carcinogens. This is the first experimental proof of the carcinogenic potential of an epidermodysplasia verruciformis-associated HPV-type in vivo. (Cancer Res 2005; 65(4): 1394-400)

Improved detection reveals active β-papillomavirus infection in skin lesions from kidney transplant recipients

“…34 Overall, our results indicated that E4 staining could be exploited as a marker of viral expression during b-HPVassociated skin cancer progression as reported in the HPV8 transgenic mouse model and in cervical disease for the a-genotypes. 33,[45][46][47] To extend the data obtained so far in epidermodysplasia verruciformis patients to other groups of patients at high risk of developing skin cancer, here we studied a series of skin lesions from kidney transplant recipients attending our University Hospital by systematically analyzing for the presence of b-HPV infection both at the DNA (PCR) and protein level. Using a combination of antibodies raised against the E4 and L1 proteins of the b-genotypes, we were able to visualize the completion of viral life cycle in some precancerous lesions such as actinic keratosis or at the periphery of more advanced disease.…”

Human papillomavirus infection and squamous cell carcinoma of the conjunctiva

“…A similar classification would greatly help elucidate the role of cutaneous HPV types in SCCC and skin carcinoma. The early genes of HPV8 have been shown to be expressed in the epidermis and to induce spontaneous benign and malignant skin lesions in transgenic mouse models (Schaper et al, 2005).…”

Loss of p53 or p73 in human papillomavirus type 38 E6 and E7 transgenic mice partially restores the UV-activated cell cycle checkpoints

“…The beta HPV types were first isolated in skin cancer-prone patients suffering from a rare autosomal recessive genetic disorder called epidermodysplasia verruciformis, but it is now clear that they are commonly found in the skin of healthy individuals (Pfister, 2003). Characterization of the biological properties of the products of the early genes E6 and E7 from different beta HPV types in in vitro and in vivo model has highlighted the potential carcinogenicity of these viruses (Jackson et al, 2000;Caldeira et al, 2003;Akgul et al, 2005;Dong et al, 2005;Schaper et al, 2005;Accardi et al, 2006;Michel et al, 2006). We showed that expression of E6 and E7 from the beta HPV38 in primary human keratinocytes results in inactivation of the tumour suppressor p53 and pRb and immortalization (Caldeira et al, 2003;Accardi et al, 2006).…”