The Human Papillomavirus Type 8 E2 Protein Induces Skin Tumors in Transgenic Mice

Abstract

Transgenic mice expressing early genes of the cutaneous human papillomavirus 8 (HPV8) spontaneously develop skin papillomas, epidermal dysplasia, and squamous cell carcinoma (6%). As the HPV8 protein E2 revealed transforming capacity in vitro, we generated three epidermal specific HPV8-E2-transgenic FVB/N mouse lines to dissect its role in tumor development. The rate of tumor formation in the three lines correlated with the different E2-mRNA levels. More than 60% of heterozygous line 2 mice, but none of the HPV8-negative littermates, spontaneously developed ulcerous lesions of the skin over an observation period of up to 144 weeks, beginning on average 74+/-22 weeks after birth. Most lesions presented infundibular hyperplasia and acanthosis combined with low-grade dysplasia. Severe dysplasia of the epidermis occurred in 6%. Two carcinomas revealed a sharply demarcated spindle-cell component. Only 3 weeks after a single UV irradiation, 87% of heterozygous line 2 and 36% of line 35 mice developed skin tumors. A rapidly growing invasive tumor composed of spindle cells arose 10 weeks after irradiation of a line-35 animal. The histology of skin cancers in HPV8-E2 mice is reminiscent of a subset of highly aggressive squamous cell carcinoma in immunosuppressed transplant recipients with a massive spindle-cell component.

Human Papillomavirus Load in Eyebrow Hair Follicles and Risk of Cutaneous Squamous Cell Carcinoma

“…This explanation is supported by data from HPV8 transgenic mice. Homozygous HPV8-E2 transgenic animals all spontaneously developed flat or polypous skin tumors during their first year of life in contrast to heterozygous mice (with half the viral DNA load and half viral mRNA levels), where only about 60% developed skin tumors in their second year of life (28). This is the first time that the association between viral load and risk of cutaneous SCCs has been described.…”

Keratinocyte-Specific Stat3 Heterozygosity Impairs Development of Skin Tumors in Human Papillomavirus 8 Transgenic Mice

“…Expression of the complete early genome region (CER) of HPV8 in transgenic mice was found to be sufficient for the spontaneous development of NMSC (10). In addition, our group has shown the intrinsic oncogenic potential of HPV8 E2 (11) and HPV8 E6 (12) using transgenic animals. Once more using transgenic technology, several mouse lines have been developed that express E6/E7 from other β-genotypes, such as HPV38 (13) and HPV20 (14), but HPV8 has thus far been the only cutaneous HPV type found to induce skin cancer completely on its own in the absence of any additional co-carcinogenic treatment.…”

The Role of E2 Proteins in Papillomavirus DNA Replication

“…HPV8 E2 protein suppresses 4-integrin expression and HPV16 E2 protein transcriptionally activates the promoter of a key cellular splicing factor SF2/ASF (Mole et al, 2009;Oldak et al, 2004). The expression of HPV8 E2 protein in transgenic mice can induce the formation of skin tumors through an unknown mechanism (Pfefferle et al, 2008). The E2 proteins bind to inverted repeats with consensus sequence 5' ACCGN 4 CGGT, where N 4 represents a 4 bp central sequence (Li et al, 1989).…”