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

核磷脂酰肌醇-4,5-二磷酸在乳头瘤病毒相关癌症发展中的作用。

• 批准号: 445814887
• 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
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/445814887?language=en
• 关键词: role; nuclear; phosphatidylinositol; bisphosphate; papillomavirus

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.

人乳头瘤病毒（HPV）是一个小的DNA病毒大家族，感染粘膜或皮肤上皮。致癌型HPV可在这些解剖部位致癌。不幸的是，预防性疫苗可能大大减少粘膜HPV疾病的惊人负担的希望没有达到他们的期望。因此，人们对揭示致癌HPV特有的细胞变化有着浓厚的兴趣，其总体目标是确定与癌症进展有关的新型生物标志物，以及确定治疗HPV相关肿瘤的更有效的治疗靶点。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癌蛋白的角化细胞和HPV感染的上皮中，核磷脂酰肌醇4,5-二磷酸（PI(4,5)P2）水平高，导致HPV阳性皮肤癌以及HPV16阳性宫颈上皮内瘤变和宫颈癌的核蛋白磷脂化。PI(4,5)P2水平升高似乎是致癌性HPV感染的角化细胞病变的常见现象，因为非HPV引发的皮肤肿瘤被发现为PI(4,5)P2阴性。这些发现提出了关于PI(4,5)P2在hpv诱导的表皮癌发展中的致癌作用的重要基础问题，以及这些发现是否也可以用于未来的治疗方案。因此，本提案的最终目标是评估PI(4,5)P2蛋白磷脂化在HPV介导的癌症发展中的作用，并进一步确定它是否可以作为一种可行的新型生物标志物，用于早期检测持续HPV复制，这很可能成为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。我们期望获得的数据在为鉴定新的分子途径铺平道路以及获得HPV介导的PI(4,5)P2途径改变的机制见解以及它们如何驱动上皮肿瘤发展方面具有关键意义。由于不仅磷脂代谢本身，特别是脂质结合蛋白已经成为各种人类疾病药物干预策略的有希望的新靶点，因此针对HPV阳性角质形成细胞中的这些机制可能会导致治疗HPV介导/诱导的癌症的新治疗策略。