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

高危 HPV E6：HPV 相关癌症中蛋白质伙伴关系导致永生化、生长和分化失调

• 批准号: 10599463
• 负责人: Rachel Adria Katzenellenbogen
• 金额: $ 6.71万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-04 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599463
• 关键词: Automobile Driving; Cervical; Chronology; Clinical; Data; Development; Differentiation and Growth; Disease; Etiology; Fostering; Foundations; Future; Gene Targeting; Growth; Head and Neck Cancer; Human Papilloma Virus Vaccine; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Infection; Investigation; Longevity; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Molecular; Oncogenic; Pathway interactions; Poly(A)-Binding Proteins; Preventive; Preventive vaccine; Proteins; Risk; Risk Factors; TERT gene; Target Populations; Telomerase; Therapeutic Intervention; Time; Viral; Viral Genes; Woman; Work; cancer risk; cell growth; chronic infection; clinical risk; high risk; human papilloma virus oncogene; men; prevent; protein function; senescence; uptake

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.

项目摘要/摘要： 高风险的人乳头瘤病毒（HR HPV）会导致所有癌症的5％。 反对HPV，但不到2％的全球目标人口获得了收益。 我们需要使用HP​​V相关的宫颈，肛门和颈部的男性 了解HR HPV如何建立，维持和积极感染，同时还可以推动癌症发展， 为了指导聚焦的治疗性介入，逮捕和逆向疾病。 宫颈癌最大的临床危险因素是持续的HR HPV感染。 通过协调的细胞途径失调发生，既支持感染又支持寄养 癌症发展。 与细胞蛋白的合作伙伴。 以前是CANCER中的常见HR HPV。 其蛋白质伴侣的细胞质聚（A）结合蛋白（PABPC）完全激活端粒酶和TEE 永生途径。我们目前的研究表明，NFX1-123在宫颈癌中高度表达 16E6，NFX1-123和PABPC随着时间的推移会扩增端粒酶，细胞生长和寿命 还发现NFX1-123在差异时增加了，并与16E6一起增强了细胞 区分级联，宿主和病毒基因靶标，同时保护 伴随的细胞停滞和衰老。 这将揭示增长，扩散和时间变化驱动的连接和控制 PABPC，NFX1-123和16E6的永生化也将描绘目标。 对于未来的治疗方法，这些治疗专门破坏了HPV及其癌症所需的通用途径。 我们的具体目的是：（1）确定16E6，NFX1-123和PABPC如何共同调节 增长和区分更好地建立持续感染。 HR HPV感染，以识别这些蛋白质允许区分和生长的方式 在HR HPV感染的初始基础步骤中，阐明了（2）的基础步骤。 16E6，NFX1-123和PABPC的纵向，HTERT和端粒酶的顺序增加 激活导致细胞永生化。 由于NFX1-123和PABPS的16E6，HTERT的顺序变化，端粒酶的催化亚基， 并创建一个分子致癌性进展的路线图，以反映我们的临床时间 研究将通过16E6阐明致癌途径的时间和间交织失调，并且是宿主 蛋白质伙伴还将提供有关致癌病因学和进展的fouvide基础数据 越来越常见的HPV相关癌症。