Epigenetic Effects of Epstein-Barr Virus Infection in Oral Squamous Cell Carcinoma

EB 病毒感染对口腔鳞状细胞癌的表观遗传效应

• 批准号: 8992993
• 负责人: RONA S SCOTT
• 金额: $ 36.25万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992993
• 关键词: AIDS/HIV problem; Address; Adult; Affect; Anogenital cancer; Antibodies; Area; Biological; Biological Markers; Biology; Calcium; Carcinoma; Cell Line; Cells; Cervical; Cervix Neoplasms; Characteristics; Clinical; CpG Island Methylator Phenotype; CpG Islands; DNA Methylation; Data; Deglutition; Detection; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Enteral Feeding; Epidemic; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Epstein-Barr Virus Infections; Etiology; Exhibits; Gene Expression; Gene Expression Profiling; General Population; Genes; HIV; HPV-High Risk; Head and Neck Cancer; Hearing; Human Herpesvirus 4; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Hypermethylation; Incidence; Individual; Infection; Inherited; Left; Lesion; Life; Ligands; Lymphoid; Lymphoid Tissue; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Maps; Mediating; Methylcellulose; Modeling; Modification; Molecular Profiling; Mouth Neoplasms; Mutation; Nasopharyngeal Undifferentiated Carcinoma; Nasopharynx Carcinoma; Nature; Neoplasm Metastasis; Nodal; Oncogene Proteins; Oncogenic; Oncogenic Viruses; Oral; Oral cavity; Oropharyngeal; Oropharyngeal Squamous Cell Carcinoma; Outcome; Pathogenesis; Patients; Phenotype; Population; Process; Prognostic Marker; Publishing; Relative (related person); Running; Signal Transduction; Site; Staging; TCF Transcription Factor; Testing; Tongue Carcinoma; Tonsil; Tonsillar Carcinoma; Tracheostomy Tube; Viral; Viral Genes; Viral Genome; Virus; WNT Signaling Pathway; WNT5A gene; aged; base; cancer cell; cell motility; co-infection; cofactor; genome-wide; high risk; improved; in vitro Model; keratinocyte; malignant mouth neoplasm; mouth squamous cell carcinoma; oral carcinogenesis; oral lesion; public health relevance; research study; response; therapeutic target; tongue root; trait; transcription factor; tumor; tumor progression; young man

 DESCRIPTION (provided by applicant): This proposal will investigate Epstein - Barr virus (EBV) as a cofactor in the pathogenesis of a growing subset of HPV+ oropharyngeal squamous cell carcinomas (OSCC). High risk HPV cause epithelial tumors of the cervix, anogenital tract and oropharynx, with the latter rising at epidemic rates. An increased incidence of HPV+OSCC is also observed in HIV-infected individuals. Although the etiology of cervical lesions is well understood, the development of HPV+ OSCC, predominantly arising from the tonsils and base of tongue (BOT), is not. No precursor lesions have been found in HPV-associated OSCC. Tumors develop rapidly with patients presenting with highly metastatic tumors; yet tumors are more responsive to treatment. These biological traits of OSCC differ from those observed for cervical cancers and raise the possibility for other cofactors in the etiology of HPV+ OSCC. The majority of HPV-associated oral lesions arise from the tonsils and BOT which are in close proximity to lymphoid tissues, sites where EBV persists in greater than 90% of the adult population. Indeed, we have observed that a significant number of HPV-positive BOT and tonsillar carcinomas carry EBV, suggesting that EBV may contribute to the development of OSCC. Our data indicate that EBV is able to epigenetically reprogram infected epithelial cells with characteristics that involve CpG island hypermethylation, altered differentiation, increased cell invasion, and activated Wnt signaling. Based on these observations, we hypothesize that EBV infection epigenetically reprograms epithelial cells to favor HPV pathogenesis and the metastatic phenotype observed in HPV+OSCC. Mechanistically, we propose that the EBV-induced epigenetic changes functionally replace the accumulation of mutations typically associated with the progression of HPV+ cervical cancers and provide an explanation for the rapid progression of HPV+OSCC. To test our hypothesis, experiments in aim 1 will define epigenetic alterations induced by EBV infection in non-transformed orally derived epithelial cell lines that regulate epithelial differentiation an invasion. Aim 2 will identify viral and cellular transcriptional signatures of EBV+ and HPV+ OSCC tumors associated with differentiation and invasion. Aim 3 will determine the epigenetic outcomes of EBV and HPV co-infection in organotypic raft cultures. Our studies will provide a mechanistic explanation for the distinct etiology of HPV-associated OSCC. Genome-wide maps of DNA methylation associated with EBV infection will provide a framework for EBV's contribution to the progression of oral carcinogenesis. Using biological relevant in vitro models, we will determine how EBV and HPV interact to accelerate transformation processes and increase invasiveness. Finally, we will identify a set of virally mediated alterations that can sere as biomarkers for detection, prognostic indicators for disease progression, and as therapeutic targets of HPV+ and EBV+ oral cancers including those that arise in the context of HIV/AIDS.

 描述（由申请人提供）： 该提案将在HPV+口咽鳞状细胞癌（OSCC）的越来越多的发病机理中研究Epstein -Barr病毒（EBV）作为辅助因子。高风险HPV会导致子宫颈，肛门生殖道和口咽的上皮肿瘤，后来以流行率升高。在HIV感染的个体中，HPV+OSCC的发生率也增加。尽管颈椎病变的病因良好，但HPV+ OSCC的发展主要是由扁桃体和舌头（BOT）引起的。在与HPV相关的OSCC中未发现前体病变。肿瘤迅速发展，患者患有高度转移性肿瘤。然而，肿瘤对治疗的反应更快。 OSCC的这些生物学特征与宫颈癌观察到的生物特征不同，并提高了HPV+ OSCC病因中其他辅助因子的可能性。大多数与HPV相关的口腔病变来自扁桃体和机器人，这些扁桃体和机器人与淋巴组织非常接近，EBV持续超过90％的成人人群的部位。确实，我们已经观察到大量的HPV阳性机器人和扁桃体癌携带EBV，这表明EBV可能有助于OSCC的发展。我们的数据表明，EBV能够表观遗传重新编程感染的上皮细胞，其特征涉及CPG岛高甲基化，改变分化，增加细胞浸润和激活的Wnt信号传导。基于这些观察结果，我们假设EBV感染表观遗传重新编码上皮细胞有利于HPV发病机理和在HPV+OSCC中观察到的转移表型。从机械上讲，我们建议EBV诱导的表观遗传变化在功能上取代了通常与HPV+宫颈癌进展相关的突变的积累，并为HPV+ OSCC的快速发展提供了解释。为了检验我们的假设，AIM 1中的实验将定义由EBV感染引起的表观遗传学改变，在未转化的口服的上皮细胞系中，调节上皮分化为侵袭。 AIM 2将确定与分化和侵袭相关的EBV+和HPV+ OSCC肿瘤的病毒和细胞转录特征。 AIM 3将确定有机筏培养物中EBV和HPV共感染的表观遗传结果。我们的研究将为HPV相关OSCC的独特病因提供机械解释。与EBV感染相关的DNA甲基化的全基因组图将为EBV对口腔癌变发展的贡献提供框架。使用生物学相关的体外模型，我们将确定EBV和HPV如何相互作用以加速转化过程并提高侵入性。最后，我们将确定一组虚拟介导的变化，可以将其作为检测的生物标志物，疾病进展的预后指标，以及HPV+和EBV+口服癌症的治疗靶标，包括在HIV/AIDS背景下出现的癌症。