The role of nuclear phosphatidylinositol-4,5-bisphosphate in papillomavirus associated cancer development.

人乳头瘤病毒(HPV)是一大类小的DNA病毒，可感染粘膜或皮肤上皮细胞。致癌的HPV类型可以在这些解剖部位导致癌症。令人遗憾的是，预防性疫苗可能大幅减轻粘膜HPV疾病的巨大负担的希望未能达到他们的预期。因此，人们对揭示致癌HPV特有的细胞变化非常感兴趣，总的目标是识别与癌症进展有关的新生物标记物，以及识别更有效的治疗HPV相关肿瘤的靶点。持续性乳头瘤病毒感染患者的癌症进展机制尚不清楚。最近，我们发现在表达HPV癌蛋白的角质形成细胞和HPV感染的上皮细胞中，核磷脂酰肌醇-4，5-二磷酸(PI(4，5)P2)水平较高，导致HPV阳性皮肤癌以及HPV16阳性宫颈上皮内瘤变和宫颈癌中核蛋白的磷脂化。在致癌HPV感染的角质形成细胞病变中，PI(4，5)P2水平升高似乎是一种普遍现象，因为未被HPV触发的皮肤肿瘤被发现PI(4，5)P2阴性。这些发现提出了重要的基础性问题，即PI(4，5)P2在HPV诱导的表皮癌发展中的致癌作用，以及这些发现是否也可能用于未来的治疗方案。因此，这项建议的最终目标是评估PI(4，5)P2蛋白磷脂在HPV介导的癌症发生中的作用，并进一步确定它是否可以作为一种可行的新的生物标记物，用于早期检测HPV的持续复制，这也可能被证明是一种有效的癌症预防策略。为此，我们将使用细胞模型以及人类肿瘤组织/肿瘤活检来研究PI(4，5)P2水平升高对角质形成细胞生理的特定影响。我们期望所获得的数据将为鉴定新的分子通路铺平道路，并获得对HPV介导的PI(4，5)P2通路的改变及其如何驱动上皮性肿瘤发展的机制的深入了解。由于不仅磷脂代谢本身，尤其是脂结合蛋白已成为各种人类疾病药物干预策略的新靶点，针对HPV阳性角质形成细胞的这些机制可能会为HPV介导/诱导的癌症的治疗提供新的治疗策略。

Human papillomaviruses (HPV) constitute of a large family of small DNA viruses, which infect either mucosal or cutaneous epithelia. Oncogenic HPV types can cause cancer at these anatomic sites. Hopes that prophylactic vaccines might substantially reduce the staggering burden of mucosal HPV disease have unfortunately fallen short off their expectations. Therefore, there is an intense interest in unravelling cellular changes unique for oncogenic HPV with the overall goal to identify novel biomarkers in respect to cancer progression as well as the identification of more effective therapeutic targets for the treatment of HPV-associated tumors. The mechanism of cancer progression in patients with persistent papillomavirus infections is not well understood. Recently, we found that nuclear phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) levels are high in keratinocytes expressing HPV oncoproteins and in HPV-infected epithelia, resulting in the phospholipidation of nuclear proteins in HPV positive skin cancer as well as HPV16 positive cervical intraepithelial neoplasia and cervical cancer. Elevated PI(4,5)P2 levels seem to be a common phenomenon in oncogenic-HPV infected keratinocytic lesions, since skin tumors which are not triggered by HPV, were found to be PI(4,5)P2 negative. These findings raise important fundamental questions regarding the oncogenic role of PI(4,5)P2 in HPV-induced epidermal cancer development, and whether these findings may also be put to use in future treatment regimens. Thus, the ultimate goal of this proposal is to assess the role of protein-phospholipidation with PI(4,5)P2 in HPV-mediated cancer development, and further determine whether it may serve as a viable novel biomarker for early detection of persistent HPV replication, which very well may turn out to be an effective cancer prevention strategy as well. To this end, we will use cellular models as well as human tumor tissues / tumor biopsies to investigate the specific effects of elevated PI(4,5)P2 levels on keratinocyte physiology. We expect the acquired data to be of pivotal importance in paving the way for the identification of novel molecular pathways and for gaining mechanistic insights into HPV mediated alterations of PI(4,5)P2 pathways and how they may drive epithelial tumor development. Since not only the phospholipid metabolism per se, but also lipid-binding proteins in particular have emerged as promising new targets for pharmacological intervention strategies in various human diseases, targeting these mechanisms in HPV positive keratinocytes may lead to new therapeutic strategies for the treatment of HPV-mediated/induced cancers.