Beta HPV38 oncoproteins act with a hit-and-run mechanism in ultraviolet radiation-induced skin carcinogenesis in mice
Cutaneous beta human papillomavirus (HPV) types are suspected to be involved, together with ultraviolet (UV) radiation, in the development of non-melanoma skin cancer (NMSC). Studies in in vitro and in vivo experimental models have highlighted the transforming properties of beta HPV E6 and E7 oncopr...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
January 11, 2018
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| In: |
PLoS pathogens
Year: 2018, Volume: 14, Issue: 1 |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1006783 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.ppat.1006783 Verlag, lizenzpflichtig, Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764406/ 
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| Author Notes: | Daniele Viarisio, Karin Müller-Decker, Rosita Accardi, Alexis Robitaille, Matthias Dürst, Katrin Beer, Lars Jansen, Christa Flechtenmacher, Matthias Bozza, Richard Harbottle, Catherine Voegele, Maude Ardin, Jiri Zavadil, Sandra Caldeira, Lutz Gissmann, Massimo Tommasino |
| Summary: | Cutaneous beta human papillomavirus (HPV) types are suspected to be involved, together with ultraviolet (UV) radiation, in the development of non-melanoma skin cancer (NMSC). Studies in in vitro and in vivo experimental models have highlighted the transforming properties of beta HPV E6 and E7 oncoproteins. However, epidemiological findings indicate that beta HPV types may be required only at an initial stage of carcinogenesis, and may become dispensable after full establishment of NMSC. Here, we further investigate the potential role of beta HPVs in NMSC using a Cre-loxP-based transgenic (Tg) mouse model that expresses beta HPV38 E6 and E7 oncogenes in the basal layer of the skin epidermis and is highly susceptible to UV-induced carcinogenesis. Using whole-exome sequencing, we show that, in contrast to WT animals, when exposed to chronic UV irradiation K14 HPV38 E6/E7 Tg mice accumulate a large number of UV-induced DNA mutations, which increase proportionally with the severity of the skin lesions. The mutation pattern detected in the Tg skin lesions closely resembles that detected in human NMSC, with the highest mutation rate in p53 and Notch genes. Using the Cre-lox recombination system, we observed that deletion of the viral oncogenes after development of UV-induced skin lesions did not affect the tumour growth. Together, these findings support the concept that beta HPV types act only at an initial stage of carcinogenesis, by potentiating the deleterious effects of UV radiation., Many epidemiological and biological findings support the hypothesis that beta HPV types cooperate with UV radiation in the induction of NMSC, the most common form of human cancer. We have previously shown that K14 HPV38 E6/E7 Tg mice, when exposed to long-term UV radiation, developed NMSC, whereas WT animals subjected to identical treatments did not develop any type of skin lesions. Here, we show that the high skin cancer susceptibility of these Tg animals tightly correlates with their tendency to accumulate UV-induced mutations in genes that are frequently mutated in human NMSC. Importantly, deletion of the HPV38 E6 and E7 genes in existing skin lesions did not affect the further growth of the cancer cells. Together, these findings support the model that beta HPV infection is a co-factor in skin carcinogenesis, facilitating the accumulation of the UV-induced DNA mutations. |
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| Item Description: | Gesehen am 20.04.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1006783 |