Significance of epigenetic changes for betaHPV mediated skin carcinogenesis.

人类乳头瘤病毒(HPV8型)与非黑色素瘤皮肤癌的发生有关。然而，潜在的致癌机制仍未解决。癌前光化性角化病的病毒流行率和病毒载量高于鳞状细胞皮肤癌，表明BetaHPV在癌症发生中的作用。β-HPV癌蛋白在体外培养系统和转基因小鼠中的组成性表达有助于我们理解β-HPV癌基因的致癌机制。核心假设是，BetaHPV可能通过一种打了就跑的机制在皮肤癌发生中发挥作用，这一点仍需在体内进行实验证明。因此，第一个目标是为HPV8建立一种有条件的、可诱导的小鼠模型，以分析一旦病毒基因被激活仅短时间内皮肤肿瘤的形成和癌细胞干细胞的维持。体外可诱导载体系统的额外实验将支持致癌信号的机制分析。第二个目标是深入表征感染BetaHPV的皮肤中的表观遗传标记，如组蛋白修饰和DNA甲基化，这将与干细胞活性的变化相关。

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.