UV and Cutaneous Papillomavirus Infection cooperate in Non-Melanoma Skin Cancer Development

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

Les Diablerets

Workshop; Perspectives on skin cancer prevention; 2018

European Molecular Biology Organization (EMBO)

UV radiation is one major factor in the multi-step process of NMSC development, but cutaneous HPVs have also been suggested as co-factors. The rodent Mastomys coucha is naturally and persistently infected with the cutaneous papillomavirus MnPV, the etiological agent for the spontaneous development of both benign and malignant skin lesions. We investigated the relationship between MnPV infection and UV radiation in the progression of NMSC in this natural animal model.Only MnPV+ but not virus-free Mastomys developed cutaneous SCCs after chronic UVB irradiation. Histology revealed two types of SCCs: well-differentiated tumors with high amounts of transcriptionally active MnPV-DNA and poorly differentiated tumors with very low amounts or even absent MnPV-DNA, despite seropositivity of the animals against MnPV-L1. Co-localization of viral DNA and γH2AX foci in tumors indicated the interference of MnPV with DNA repair. Notably, like in humans, Trp53 was mutated in most SCCs, especially when poorly differentiated. Two hot-spot mutations completely impaired its transactivation efficiency in functional assays. A correlation between mutated p53 and EMT markers in poorly differentiated SCCs points towards dedifferentiation after loss of functional p53. The viral DNA load also decreased in less differentiated areas of such tumors.MnPV favors SCC development by impairing the UVB-induced damage response, leading to an accumulation of mutations in dedifferentiated tumor cells. Here, MnPV is no longer required to maintain the malignant phenotype and is lost. This is the first study showing a ?hit-and-run? mechanism for a cutaneous papillomavirus in NMSC development.