Tumorigenesis by the Epstein Barr Virus

EB 病毒引起的肿瘤发生

基本信息

批准号：
10696218
负责人：
NANCY JOAN RAAB-TRAUB
金额：
$ 34.72万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696218
关键词：
Affect Agar Alternative Splicing Biological Assay Biological Process Bromodeoxyuridine Cell Line Cell physiology Cell secretion Cells ChIP-seq Coculture Techniques Collaborations CpG Islands DNA Deposition Development Epithelial Cells Epithelium Epstein-Barr Virus Infections Epstein-Barr Virus latency Exons Gene Cluster Gene Expression Gene Silencing Genes Genetic Transcription Genomics Goals Growth Human Herpesvirus 4 Human Papillomavirus Human papilloma virus infection Immunoprecipitation In Vitro Incidence Infection LMP1 Malignant Neoplasms Malignant neoplasm of cervix uteri Membrane Proteins Methylation MicroRNAs Migration Assay Mus NOD/SCID mouse Nuclear Pore Complex Oncogenic Oral Oropharyngeal Pathway interactions Population Process Production Property Protein Isoforms Protein Secretion Proteins RNA RNA Splicing Research Signal Pathway Small RNA Stains Structure Testing Throat Cancer Transcript Ubiquitination Untranslated RNA Viral Viral Genes Viral Oncogene Viral Proteins Virus Virus Diseases Visualization Western Blotting Xenograft procedure bisulfite sequencing cell growth co-infection exosome experimental study extracellular vesicles in vivo keratinocyte mRNA sequencing novel strategies opportunistic pathogen oral HPV oral infection permissiveness persistent EBV infection programs promoter transcriptome sequencing transforming virus tumor tumorigenesis uptake viral genomics virus related cancer whole genome

项目摘要

Project 4 Project Summary Abstract The goal of this project is to continue to determine how EBV modulates cell growth with particular focus on the BART long noncoding RNAs and to identify potential effects of the presence of EBV infected cells on the growth and expression of HPV infected cells. We have previously shown profound effects of the viral oncogenes, latent membrane proteins 1 and 2, on the growth of cells through activation of distinct signaling pathways and effects on protein levels through ubiquitination and determined that these proteins are secreted in exosomes and can be transferred to uninfected cells. Recently, we have utilized RNASeq to analyze total cellular expression in the AGS epithelial cell line, with or without EBV infection, grown in vitro and as tumors in NOD SCID mice in comparison with the C666 NPC cell line, and the NPC xenografts C15 and C17. The majority of the identified canonical pathways based on two fold changes in expression had decreased activity in vivo. EBV expression was also distinct with greatly increased transcription of the BART non coding RNAs in both NPC and the AGS cells. The significant expression of the viral BART nc RNAs in vivo in the absence of the EBV transforming proteins suggests that they are contributing factors to tumorigenesis. Their effects and potential mechanisms of action are a major focus of this application. EBV persistent infection in the oropharynx has several states of infection with cells that express multiple viral proteins including LMP1 and LMP2, cells that are restricted to BART miRNA and lnc RNA, and cells with some replicative reactivation. It is likely that through EV shedding, EBV may greatly impact other oropharyngeal viral infections. Importantly, HPV throat cancer is now the most rapidly increasing virally associated cancer. The almost universal oral infection with EBV could likely modulate the growth and cellular expression of HPV infected cells and potentially enhance their oncogenic properties. The in vivo interactions of EBV and HPV have not yet been defined. This proposal will determine how the distinct latent EBV infections or permissive infection alter the growth and expression of HPV infected cells.

项目4 项目概要摘要该项目的目标是继续确定 EBV 如何调节细胞生长，特别关注 BART 长非编码 RNA 并鉴定 EBV 感染细胞的存在对 HPV感染细胞的生长和表达。我们之前已经展示了病毒的深远影响癌基因、潜在膜蛋白 1 和 2 通过激活不同的信号传导影响细胞生长通过泛素化对蛋白质水平的途径和影响，并确定这些蛋白质是分泌的存在于外泌体中，可以转移到未感染的细胞中。最近，我们利用 RNASeq 来分析总 AGS 上皮细胞系中的细胞表达，无论有或没有 EBV 感染，在体外生长并作为肿瘤 NOD SCID 小鼠与 C666 NPC 细胞系以及 NPC 异种移植物 C15 和 C17 进行比较。这大多数基于表达两倍变化确定的经典途径活性降低体内。 EBV 表达也很明显，BART 非编码 RNA 的转录大大增加 NPC 和 AGS 细胞。病毒 BART nc RNA 在体内的显着表达 EBV 转化蛋白表明它们是肿瘤发生的促成因素。它们的作用和潜在的作用机制是该应用的主要焦点。口咽部的 EBV 持续感染具有表达多种病毒的细胞的几种感染状态包括 LMP1 和 LMP2 在内的蛋白质、仅限于 BART miRNA 和 lnc RNA 的细胞以及具有某些复制性重新激活。通过 EV 脱落，EB 病毒可能会极大地影响其他口咽病毒感染。重要的是，HPV 喉癌现在是增长最快的病毒相关癌症。这几乎普遍的 EBV 口腔感染可能会调节 HPV 的生长和细胞表达感染细胞并可能增强其致癌特性。 EBV 和 HPV 的体内相互作用尚未被定义。该提案将确定不同的潜伏 EBV 感染或许可性感染如何感染改变 HPV 感染细胞的生长和表达。