The Interplay of UV and Cutaneous Papillomavirus Infection in Non-Melanoma Skin Cancer Development in the animal model Mastomys coucha

RÖSL, FRANK; FLECHTENMACHER, CHRISTA; BRASPENNING-WESCH, ILONA; VINZON, SABRINA EUGENIA; GRÖNE, HERMANN-JOSEF; STEPHAN, SONJA; AKGÜL, BAKI; NIEBLER, MARTINA; HASCHE, DANIEL

Heidelberg

Conferencia; Hallmarks of Skin Cancer; 2017

German Cancer Research Center

Objectives: UV radiation is one major factor in the development of non-melanoma skin cancer (NMSC). Cutaneous HPVs have also been 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), which was 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. In vitro systems were used to understand the biological effects of hot-spot mutations on p53 and induced tumors.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 tumors either with very low viral loads or even with an absence of any MnPV-DNA, despite seropositivity against MnPV-L1. Co-localization of viral DNA and γH2AX foci in tumor sections indicates the interference of MnPV with DNA repair. While this effect - in vitro - may be attributed to MnPV E6/E7, like most cutaneous HPVs types, E6 is not targeting p53 for degradation as known for high-risk mucosal HPVs. Notably, Trp53 was mutated in most SCCs, whereby poorly differentiated SCCs were more frequently affected. Like in humans, most mutations were found within the DNA-binding domain of p53 and two hot-spot mutations completely impaired the transactivation efficiency in functional assays. A correlation between mutated p53 and epithelial-mesenchymal transition (EMT) markers points towards dedifferentiation after loss of functional p53.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. This is the first report showing a ?hit-and-run? mechanism for a cutaneous papillomavirus in the development of NMSC.