High-risk HPV E6: dysregulation of immortalization, growth, and differentiation through protein partnerships in HPV-associated cancers

项目摘要/摘要 高危人类乳头瘤病毒(HR HPV)导致了5%的癌症。有预防性疫苗 针对HPV，但只有不到2%的世界目标人口接种了这种疫苗。这使得数以百万计的女性 以及有患HPV相关宫颈癌、肛门癌和头颈癌风险的男性。我们需要了解 HR HPV如何建立和维持活跃的感染，同时也推动癌症的发展，以便 指导有重点的治疗干预措施，以预防、遏制和逆转疾病。 宫颈癌的最大临床风险因素是持续的HR HPV感染。这种坚持不懈 通过细胞通路的协调失调发生，细胞通路既支持感染又促进癌症 发展。这种失调的背后是要求HPV癌基因E6和E7与 细胞蛋白质。我们的工作集中在HPV16型(16E6)的E6癌基因上，HPV16E6是最常见的HR HPV型在癌症中的作用。此前，我们发现16E6需要细胞蛋白NFX1-123及其蛋白 伴侣胞浆多聚(A)结合蛋白(PABPC)，以充分激活端粒酶和永生化 路径。我们目前的研究表明，NFX1-123在宫颈癌中高表达，16E6， 随着时间的推移，NFX1-123和PABPC可以放大端粒酶、细胞生长和寿命。我们还发现， NFX1-123在分化过程中增加，并与16E6一起增强细胞分化级联反应 以及它们的宿主和病毒基因靶点，同时防止伴随的细胞停滞和 衰老。这些发现为将发现连通性的新层次的调查创造了视线 和控制生长和分化，以及推动和加速永生的时间变化 PABPC、NFX1-123和16E6。这些结果还将为未来的治疗勾勒出目标，特别是 干扰人乳头瘤病毒及其癌症所需的通用途径。 我们的具体目标是：(1)确定16E6、NFX1-123和PABPC如何在共同调节中发挥作用 生长和分化，以更好地建立持续感染。我们将模仿建立 HR HPV感染以确定这些蛋白质允许分化和生长的功能方式 在HR HPV感染的最初、基础步骤中协调一致。(2)阐明了纵向、纵向、纵向的作用机制。 16E6、NFX1-123和PABPC依次增加端粒酶和端粒酶。端粒酶激活导联 为了细胞的永生。我们将利用长期的细胞研究来确定 端粒酶的催化亚单位hTERT，由于16E6与NFX1-123和PABPC结合，并创建了路线图 反映临床年表的分子致癌进展。我们建议的研究将阐明 16E6及其宿主蛋白伙伴对致癌途径的时间和相互交织的失调；他们将 还提供了关于日益常见的HPV的致癌病因和进展的基础数据- 相关癌症。

PROJECT SUMMARY/ABSTRACT High-risk human papillomaviruses (HR HPVs) cause 5% of all cancers. There are preventive vaccines against HPV, but less than 2% of the world's target population has received them. This leaves millions of women and men at risk for HPV-associated cervical, anogenital, and head and neck cancers. We need to understand how HR HPV establishes and maintains an active infection, while also driving cancer development, in order to guide focused therapeutic interventions to prevent, arrest, and reverse disease. The greatest clinical risk factor for cervical cancer is a persistent HR HPV infection. This persistence occurs through coordinated dysregulation of cellular pathways, which both support the infection and foster cancer development. Underlying this dysregulation is the requirement that the HPV oncogenes E6 and E7 partner with cellular proteins. Our work has focused on the E6 oncogene from HPV type 16 (16E6), the most common HR HPV type in cancers. Previously, we found that 16E6 required the cellular protein NFX1-123, and its protein partners cytoplasmic poly(A) binding proteins (PABPCs), to fully activate telomerase and the immortalization pathway. Our current studies revealed that NFX1-123 is highly expressed in cervical cancers, and together 16E6, NFX1-123, and PABPCs amplify telomerase, cellular growth, and longevity over time. We also discovered that NFX1-123 is increased during differentiation and, together with 16E6, augments cellular differentiation cascades and their host and viral gene targets while simultaneously protecting against concomitant cellular arrest and senescence. These findings create a sightline for a new level of investigation that will uncover the connectivity and control of growth and differentiation and the temporal changes driving and accelerating immortalization by PABPCs, NFX1-123, and 16E6. These results will also delineate targets for future treatments that specifically disrupt universal pathways required for HPV and its cancers. Our specific aims are: (1) Determine how 16E6, NFX1-123, and PABPCs work together in co-regulating growth and differentiation to better establish a persistent infection. We will mimic the initial steps of establishing a HR HPV infection to identify the way in which these proteins function to permit both differentiation and growth in concert during the initial, foundational steps of a HR HPV infection. (2) Elucidate the mechanism of longitudinal, sequential increases of hTERT and telomerase by 16E6, NFX1-123, and PABPCs. Telomerase activation leads to cellular immortalization. We will leverage long-term cellular studies to determine the sequential changes to hTERT, the catalytic subunit of telomerase, due to 16E6 with NFX1-123 and PABPCs and to create a roadmap of molecular oncogenic progression that mirrors clinical chronology. Our proposed studies will elucidate the temporal and interwoven dysregulation of oncogenic pathways by 16E6 and its host protein partners; they will also provide foundational data on the oncogenic etiology and progression of increasingly common HPV- associated cancers.