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Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8

Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8
Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8
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.
0008-5472
1394-1400
Schaper, Inke Diana
3c83a22b-953c-4366-a427-6ec046469307
Marcuzzi, Gian Paolo
ba3d552f-da25-464a-9e80-138fccca7016
Weissenborn, Sönke Jan
3e1238da-f609-4b6a-a0a6-94c43e489480
Kasper, Hans Udo
2d364b14-7557-4711-a792-0513b9eaaa41
Dries, Volker
00945075-ca90-42f0-9b3b-7fe12f1fe5d1
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
Fuchs, Pawel
19ef716e-4017-46b6-86df-926e996c3dd3
Pfister, Herbert
d2451d93-a9e1-4e78-a37e-e9c2cdbba0db
Schaper, Inke Diana
3c83a22b-953c-4366-a427-6ec046469307
Marcuzzi, Gian Paolo
ba3d552f-da25-464a-9e80-138fccca7016
Weissenborn, Sönke Jan
3e1238da-f609-4b6a-a0a6-94c43e489480
Kasper, Hans Udo
2d364b14-7557-4711-a792-0513b9eaaa41
Dries, Volker
00945075-ca90-42f0-9b3b-7fe12f1fe5d1
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
Fuchs, Pawel
19ef716e-4017-46b6-86df-926e996c3dd3
Pfister, Herbert
d2451d93-a9e1-4e78-a37e-e9c2cdbba0db

Schaper, Inke Diana, Marcuzzi, Gian Paolo, Weissenborn, Sönke Jan, Kasper, Hans Udo, Dries, Volker, Smyth, Neil, Fuchs, Pawel and Pfister, Herbert (2005) Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8. Cancer Research, 65, 1394-1400.

Record type: Article

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.

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Published date: 1 February 2005

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Local EPrints ID: 56695
URI: https://eprints.soton.ac.uk/id/eprint/56695
ISSN: 0008-5472
PURE UUID: b89d2dcd-0a01-453c-85b6-f881e0433e08

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Date deposited: 08 Aug 2008
Last modified: 13 Mar 2019 20:34

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