Significance of epigenetic changes for betaHPV mediated skin carcinogenesis.

表观遗传变化对 betaHPV 介导的皮肤癌发生的意义。

• 批准号: 411052531
• 负责人: Professor Dr. Baki Akgül, Ph.D.
• 金额: --
• 依托单位: Institut für Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/411052531?language=en
• 关键词: Significance; epigenetic; changes; betaHPV; mediated

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.

β属的人乳头瘤病毒（β-HPV，例如HPV 8）与非黑素瘤皮肤癌的发展相关。然而，潜在的致癌机制仍然没有得到解决。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。在体外培养系统中以及在转基因小鼠中，β-HPV癌蛋白的组成型表达对我们理解β-HPV癌基因的致癌机制做出了重大贡献。核心假设是betaHPV可能通过打了就跑的机制在皮肤癌发生中起作用，这仍然需要在体内实验证明。因此，第一个目标是产生HPV 8的条件性和诱导性小鼠模型，以分析一旦病毒基因仅在短时间内被激活，皮肤肿瘤形成和癌症干细胞维持。体外诱导型载体系统的其他实验将支持致癌信号的机制分析。第二个目标是深入表征表观遗传标记，如betaHPV感染皮肤中的组蛋白修饰和DNA甲基化，这将与干细胞活性的变化相关。