Significance of epigenetic changes for betaHPV mediated skin carcinogenesis.

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Human papillomaviruses of genus beta (beta-HPV, e.g. HPV8) are associated with the development of non-melanoma skin cancer. The underlying oncogenic mechanism is, however, still unresolved. Viral prevalence rates and viral loads are higher in precancerous actinic keratoses than in squamous cell skin cancers pointing to a role of betaHPV in cancer initiation. Constitutive expression of beta-HPV oncoproteins in in vitro culture systems as well as in transgenic mice contributed significantly to our understanding of the oncogenic mechanisms of betaHPV oncogenes. The central hypothesis is that betaHPV may act in skin carcinogenesis through a hit-and-run mechanism, which still has to be experimentally proven in vivo. Therefore, the first objective is to generate a conditional and inducible mouse model for HPV8 to analyse skin tumor formation and cancer stem cell maintenance once viral genes have been activated only for a short period of time. Additional experiments with inducible vector systems in vitro will support the mechanistic analysis of oncogenic signals. The second objective is the in-depth characterization of epigenetic markers such as histone modifications and DNA methylation in betaHPV infected skin, which will be correlated with changes in stem cell activity.