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

Würzburg

Congreso; 28th Annual Meeting of the Society for Virology; 2018

Gesellschaft für Virologie e. V. (GfV, Society for Virology); Deutsche Vereinigung zur Bekämpfung der Viruskrankheiten e. V. (DVV, German Association for the Control of Virus Diseases)

ObjectivesUV 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 the cutaneous Mastomys natalensis papillomavirus (MnPV), 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.MethodsMnPV+ 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 UV-induced hot-spot mutations regarding p53 function and tumor phenotype.ResultsOnly MnPV+ UVB-irradiated Mastomys developed cutaneous squamous cell carcinomas (SCCs). 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 tumor sections indicates the interference of MnPV with DNA repair. While this effect may be attributed to MnPV E6/E7, like for mostcutaneous 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 its transactivation efficiency in functional assays. A correlation between mutated p53 and epithelial-mesenchymal transition (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.ConclusionMnPV 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 and is lost. This is the first study showing a ?hit-and-run? mechanism for a cutaneous papillomavirus in the development of NMSC.