CONICET | Buscador de Institutos y Recursos Humanos

Objectives:UV radiation is one major factor in the development of non-melanoma skin cancer (NMSC). Cutaneous HPVs have been also suggested as co-factors in the multi-step process of skin carcinogenesis. The African rodent Mastomys coucha is naturally and persistently infected with Mastomys natalensis papillomavirus (MnPV), shown to be the etiological agent for the spontaneous development of both benign and malignant skin lesions. In the present study, we investigated the relationship between MnPV infection and UV radiation in the progression of NMSC in this natural animal model.Methods:MnPV+ animals and MnPV- controls were chronically exposed to UVB radiation. Tumors were characterized in histological and molecular terms. In parallel, the effect of UV on serology and DNA damage was examined. Results:Only MnPV+ UVB-irradiated Mastomys developed SCCs. Histological examination revealed two types of cutaneous SCCs: well-differentiated tumors with high amounts of transcriptionally active MnPV-DNA and poorly differentiated SCCs either with very low viral loads or even with an absence of any MnPV-DNA, despite seropositivity against MnPV-L1. Notably, Trp53 was mutated in most SCCs, whereby poorly differentiated SCCs were more frequently affected. Most mutations were found within the DNA-binding domain of p53 that completely impaired the transactivation efficiency in functional assays. Moreover, co-localization of viral DNA and γH2AX foci in tumor sections indicate the interference of MnPV with DNA repair.Conclusion:MnPV favors SCC development by impairing the UVB-induced damage response. This leads to an accumulation of mutations (e.g. in Trp53) in dedifferentiated tumor cells. Here, MnPV is no longer required to maintain the malignant phenotype.