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

项目概要/摘要： 高危人乳头瘤病毒（HR HPV）导致5%的癌症。有预防性疫苗 目前，世界上只有不到2%的目标人群接受了这种疫苗。这使得数百万 女性和男性有患HPV相关宫颈癌、肛门生殖器癌和头颈癌的风险。我们需要 了解HR HPV如何建立和维持活动性感染，同时也推动癌症发展， 以指导有针对性的治疗干预，以预防、阻止和逆转疾病。 宫颈癌的最大临床危险因素是持续的HR HPV感染。这种坚持 发生通过协调失调的细胞途径，这既支持感染和促进 癌症发展这种失调的基础是HPV癌基因E6和E7 与细胞蛋白质结合。我们的工作主要集中在HPV 16型（16 E6）的E6癌基因上， 常见的HR HPV类型。以前，我们发现16 E6需要细胞蛋白NFX 1 -123， 其蛋白质与细胞质多聚腺苷酸结合蛋白（PABPC）结合，以完全激活端粒酶和细胞质多聚腺苷酸结合蛋白（PABPC）。 永生化途径我们目前的研究表明，NFX 1 -123在宫颈癌中高度表达， 16 E6、NFX 1 -123和PABPC一起随着时间的推移增强端粒酶、细胞生长和寿命。我们 还发现NFX 1 -123在分化过程中增加，并与16 E6一起增强细胞增殖， 分化级联及其宿主和病毒基因靶标，同时保护免受 伴随的细胞停滞和衰老。这些发现为新的调查水平创造了视线 这将揭示生长和分化的连通性和控制，以及驱动 以及通过PABPC、NFX 1 -123和16 E6加速永生化。这些结果也将描绘目标 用于未来的治疗，专门破坏HPV及其癌症所需的通用途径。 我们的具体目标是：（1）确定16 E6，NFX 1 -123和PABPC如何共同调节 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，以确定这些蛋白质发挥功能以允许分化和生长的方式 在HR HPV感染的初始基础步骤中一致。(2)阐明 通过16 E6、NFX 1 -123和PABPC的hTERT和端粒酶的纵向、顺序增加。端粒酶 激活导致细胞永生化。我们将利用长期的细胞研究来确定 由于16 E6与NFX 1 -123和PABPC导致端粒酶催化亚基hTERT的连续变化 并建立一个反映临床时间顺序的分子致癌进展路线图。我们提出的 研究将阐明16 E6及其宿主对致癌途径的暂时性和交织性失调 蛋白质伴侣;他们还将提供致癌病因学和进展的基础数据， 越来越常见的HPV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.