权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

HPV E6 and NFX1-123 in differentiation, cell regulation, and cancer

HPV E6 和 NFX1-123 在分化、细胞调节和癌症中的作用

基本信息

批准号：
9265426
负责人：
Rachel Adria Katzenellenbogen
金额：
$ 40.26万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
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 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265426
关键词：
Adult Affect Anogenital venereal warts Architecture Binding Biological Markers Biology Cancer Model Cancer cell line Cell Differentiation process Cell Proliferation Cells Cervical dysplasia Clinical DNA Data Development Differentiated Gene Differentiation Antigens Differentiation and Growth Disease Epithelial Epithelial Cells Epithelium Equilibrium Gene Expression Gene Expression Regulation Gene Proteins Gene Targeting Generations Genes Genetic Transcription Genital system Genotype Goals HPV-High Risk Human Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Immunization Incidence Infection Life Cycle Stages Longevity Low risk HPV Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Modeling Mucous Membrane Normal Cell Oncogenes Oncogenic Papillomavirus Infections Pathway interactions Patients Poly(A)-Binding Proteins Positioning Attribute Post-Transcriptional Regulation Preventive Preventive vaccine Process Productivity Proliferating Proteins RNA Processing Regulation Risk Role Sampling Sexually Transmitted Diseases Structural Protein TERT gene Teenagers Telomerase Time Transcription Initiation Tumor Virus Infections Viral Virion Woman Women&apos s Health Work base cell growth clinical biomarkers high risk keratinocyte male men overexpression penis foreskin protein degradation protein function public health relevance screening sexual debut therapeutic target tumor tumor progression tumorigenesis uptake validation studies viral DNA whole genome

项目摘要

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) affects up to 75% of adults and is categorized as high risk (HR) or low risk (LR) based on its association with cancer. Although there are two preventive vaccines against two (HR HPV 16, 18) or four (HR HPV 16, 18 and LR HPV 6, 11) HPV genotypes, immunizations in the USA have had poor uptake and completion. This leaves many women and men at continued risk of HPV-associated cancers, some of which are increasing in incidence. The HR HPV oncogenes E6 and E7 drive cellular immortalization; HR E6 specifically partners with several endogenous proteins to dysregulate epithelial cells. In our own studies, we found that 16E6 interacts with the NFX1-123. Together, these proteins act post-transcriptionally to increase the expression of hTERT, the catalytic subunit of telomerase. Telomerase activation is critical for cellular immortalization, is a key ste in cancer development, and is universally detected in HPV-associated cancers. We are now prepared to study other genes and cellular pathways regulated by the concerted actions of 16E6 and NFX1-123. In whole-genome expression microarray and validation studies, we identified several differentiation genes and a master differentiation regulator, Notch1, as upregulated by NFX1-123 and 16E6. Interestingly, this increase in differentiation pathway genes did not lead to cellular growth arrest. These data put us in a strong position to study the combined roles of 16E6 and NFX1-123 in the viral life cycle, the cell, cancer development and progression. Our specific aims are to: (1) Determine the mechanism of gene regulation by 16E6 and NFX1-123. We have identified post-transcriptional gene regulation of hTERT as a new and critical role for 16E6 and NFX1-123. We hypothesize that NFX1-123 and 16E6 function together to dysregulate other genes, with hTERT regulation as our working model. (2) Determine how HPV and NFX1-123 affect the balance of differentiation and continued cellular proliferation in epithelium. We found NFX1-123 with 16E6 increased expression of differentiation genes and Notch1, and these same cells continued to proliferate in culture. We will define how NFX1-123, 16E6, and Notch1 modulate epithelial architecture, and hypothesize the differentiation and growth arrest pathways are uncoupled to allow cellular growth and support a productive and long-lived HPV infection that leads to malignant changes over time. (3) Determine how NFX1-123 expression changes and drives HPV-associated cancer development and progression. We found increased NFX1-123 in cervical cancer cell lines and in 30% of patient tumor samples. Therefore, we hypothesize that increased NFX1-123, and its downstream gene targets, favors oncogenic progression. Using cervical dysplasia models and patient samples, we will quantify changes in NFX1-123 and identify critical points where increased NFX1-123 is needed in HPV-associated cancers. These studies will expand our understanding of HPV-driven oncogenesis and help to identify biomarkers and therapeutic targets for HPV-associated cancers

描述（由申请人提供）：人乳头瘤病毒（HPV）影响高达75%的成年人，并根据其与癌症的相关性分为高风险（HR）或低风险（LR）。虽然有两种预防性疫苗针对两种（HR HPV 16，18）或四种（HR HPV 16，18和LR HPV 6，11）HPV基因型，但美国的免疫接种率和完成率很低。这使得许多女性和男性继续面临HPV相关癌症的风险，其中一些癌症的发病率正在增加。HR HPV癌基因E6和E7驱动细胞永生化; HR E6特异性地与几种内源性蛋白质合作以失调上皮细胞。在我们自己的研究中，我们发现16 E6与NFX 1 -123相互作用。这些蛋白质一起在转录后起作用以增加端粒酶催化亚基hTERT的表达。端粒酶的活化对细胞永生化至关重要，是癌症发展的关键步骤，并且在HPV相关癌症中普遍检测到。我们现在准备研究由16 E6和NFX 1 -123协同作用调节的其他基因和细胞通路。在全基因组表达微阵列和验证研究中，我们确定了几个分化基因和一个主分化调节因子Notch 1，被NFX 1 -123和16 E6上调。有趣的是，这种分化途径基因的增加并不导致细胞生长停滞。这些数据使我们能够研究16 E6和NFX 1 -123在病毒生命周期、细胞、癌症发展和进展中的联合作用。本研究的具体目的是：（1）确定16 E6和NFX 1 -123的基因调控机制。我们已经确定hTERT的转录后基因调控是16 E6和NFX 1 -123的一个新的关键作用。我们假设NFX 1 -123和16 E6共同发挥功能，使其他基因失调，以hTERT调节作为我们的工作模型。(2)确定HPV和NFX 1 -123如何影响上皮细胞分化和持续细胞增殖的平衡。我们发现NFX 1 -123与16 E6增加了分化基因和Notch 1的表达，并且这些相同的细胞在培养中继续增殖。我们将定义NFX 1 -123，16 E6和Notch 1如何调节上皮结构，并假设分化和生长停滞途径是解偶联的，以允许细胞生长，并支持随着时间的推移导致恶性变化的生产性和长期HPV感染。(3)确定NFX 1 -123表达如何变化并驱动HPV相关癌症的发展和进展。我们在宫颈癌细胞系和30%的患者肿瘤样本中发现NFX 1 -123增加。因此，我们假设NFX 1 -123及其下游基因靶点的增加有利于致癌进展。使用宫颈不典型增生模型和患者样本，我们将量化NFX 1 -123的变化，并确定HPV相关癌症中需要增加NFX 1 -123的关键点。这些研究将扩大我们对HPV驱动的肿瘤发生的理解，并有助于确定HPV相关癌症的生物标志物和治疗靶点