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

基本信息

批准号：
10738316
负责人：
Rachel Adria Katzenellenbogen
金额：
$ 7.03万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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

项目摘要

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％。有预防疫苗反对HPV，但不到2％的全球目标人群获得了他们的收到。这留下了数百万的女人和有HPV相关的宫颈，肛门生殖器和头颈癌的男性。我们需要了解 HR HPV如何建立和保持主动感染，同时还可以推动癌症发展指导专注的治疗干预措施，以预防，逮捕和逆转疾病。宫颈癌最大的临床危险因素是持续的HR HPV感染。这种持久性通过对感染和促进癌症的细胞途径的协调失调而发生的。发展。这种失调的基础是HPV Oncogenes E6和E7与细胞蛋白。我们的工作集中在HPV 16型（16E6）的E6癌基因上，这是最常见的HR HPV类型中的癌症。以前，我们发现16E6需要细胞蛋白NFX1-123及其蛋白伴侣细胞质聚（A）结合蛋白（PABPC），以完全激活端粒酶和永生化路径。我们目前的研究表明，NFX1-123在宫颈癌中高度表达，共同表达16E6，，随着时间的流逝，NFX1-123和PABPC会扩增端粒酶，细胞生长和寿命。我们还发现 NFX1-123在分化过程中增加了，并与16E6一起增强细胞分化级联以及他们的宿主和病毒基因靶标，同时防止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，可以揭示连接性以及控制生长和分化以及驱动和加速永生的时间变化 PABPC，NFX1-123和16E6。这些结果还将描述未来治疗的目标破坏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如何共同调节生长和分化以更好地建立持续感染。我们将模仿建立的初始步骤 HR HPV感染，以识别这些蛋白质允许分化和生长的方式在HR HPV感染的最初的基础步骤中，共同进行。（2）阐明纵向， 16E6，NFX1-123和PABPC的HTERT和端粒酶的顺序增加。端粒酶激活引线到细胞永生化。我们将利用长期细胞研究来确定 HTERT是端粒酶的催化亚基，这是由于NFX1-123和PABPC的16E6，并创建路线图反映临床时间学的分子致癌进展。我们提出的研究将阐明通过16E6及其宿主蛋白伴侣对致癌途径的时间和间交织失调；他们会的还提供有关越来越常见的HPV-的致癌病因和进展的基础数据相关的癌症。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human papillomavirus 16E6 and NFX1-123 potentiate Notch signaling and differentiation without activating cellular arrest.

DOI：
10.1016/j.virol.2015.02.002
发表时间：
2015-04
期刊：
VIROLOGY
影响因子：
3.7
作者：
Vliet-Gregg, Portia A.;Hamilton, Jennifer R.;Katzenellenbogen, Rachel A.
通讯作者：
Katzenellenbogen, Rachel A.

Telomerase Induction in HPV Infection and Oncogenesis.

DOI：
10.3390/v9070180
发表时间：
2017-07-10
期刊：
Viruses
影响因子：
0
作者：
Katzenellenbogen R
通讯作者：
Katzenellenbogen R

Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes.

DOI：
10.3390/cancers13246182
发表时间：
2021-12-08
期刊：
Cancers
影响因子：
5.2
作者：
Quist KM;Solorzano I;Wendel SO;Chintala S;Wu C;Wallace NA;Katzenellenbogen RA
通讯作者：
Katzenellenbogen RA

NFX1, Its Isoforms and Roles in Biology, Disease and Cancer.