Effect of HPV16 and ART on the Epigenome Leading to AIDS-Associated Oral Cancer

HPV16 和 ART 对导致艾滋病相关口腔癌的表观基因组的影响

• 批准号: 9320526
• 负责人: Craig M Meyers
• 金额: $ 48.34万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320526
• 关键词: AIDS diagnosis; Acquired Immunodeficiency Syndrome; Acute; Adherent Culture; Affect; Amprenavir; Annual Reports; Biological Models; Biology; Cancer Burden; Carcinogenesis Mechanism; Cells; Cervix Neoplasms; Country; DNA Methylation; Disease; Epigenetic Process; Epithelial; Ethnic group; Gene Expression; Gene Expression Regulation; Genetic; Genome; Genomics; Goals; HIV; HIV antiretroviral; Head and Neck Squamous Cell Carcinoma; Highly Active Antiretroviral Therapy; Human; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Incidence; Individual; Infection; Internet; Journal of the National Cancer Institute; Knowledge; Life Cycle Stages; Lopinavir/Ritonavir; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measurement; Measures; Messenger RNA; Methylation; MicroRNAs; Modeling; Modification; Molecular; Molecular Abnormality; Mouth Diseases; Natural History; Oncogenes; Oncogenic; Oral; Oropharyngeal; Pattern; Persons; Pharyngeal structure; Premalignant; Race; Reporting; Risk; Rosa; Signal Pathway; Testing; Time; Tissues; Tobacco; Tonsil; Viral; Viral Genome; Virus Replication; Woman; antiretroviral therapy; cancer site; carcinogenesis; carcinogenicity; differential expression; epigenome; epigenomics; functional outcomes; genome-wide; keratinocyte; keratinocyte differentiation; malignant mouth neoplasm; malignant oropharynx neoplasm; men; methylome; next generation sequencing; oral HPV; oral HPV infection; oral cavity epithelium; oral tissue; public health relevance; reproductive tract; response; transcriptomics; tumorigenesis; viral DNA

 DESCRIPTION (provided by applicant): The percentage of oropharyngeal cancers associated with HPV16 infection rose from 16.3% between the years of 1984 to 1989 to 71.7% between the years of 2000 to 2004. In contrast, the number of tobacco-related oropharyngeal cancers has been steadily declining over the same time period. Similar changes have been reported in multiple countries. There have been substantial changes in the burden of cancer affecting HIV- infected individuals in the U.S. during a 12-year period spanning the introduction of highly active anti-retroviral therapy (HAART). Among these emerging malignancies, HPV-associated cancers of the oral cavity/pharynx increased significantly following an AIDS diagnosis. HPV is rapidly changing the landscape of HNSCC. However, the mechanisms and natural history of oral HPV infection and oncogenic progression is poorly understood. Extrapolation of knowledge of HPV-associated oncogenicity in the genital tract is not satisfactory to our understanding of oral HPV disease. HPV is necessary, but not sufficient cause of invasive cervical cancer. The epigenetic mark of methylation is a common hallmark of human cancer. Epigenetic studies using the proper model systems can provide significant increases in our knowledge concerning the mechanisms and signaling pathways that drive HPV infection, life cycle, and oncogenesis. Aberrant microRNAs (miRNAs) expression is becoming recognized as a new molecular mechanism of carcinogenesis. HPV-infected keratinocytes express a different set of miRNAs when compared to noninfected keratinocytes. Additionally, HPV-infected cells grown in nondifferentiating monolayer culture express a different set of miRNAs compared to HPV-infected differentiating keratinocytes. Our long-term goal is to investigate the epigenetic mechanisms of HPV-associated oral disease. HPV16 is associated with 90-95% of HNSCC. Our studies will focus on HPV16. Our hypothesis is that the effect of the HPV life cycle and carcinogenesis on the epigenomic landscape of oral epithelium is further affected by HIV antiretroviral therapy (ART). The epigenome of both the host genome and the viral genome is affected. A combination of next generation sequencing analysis of the methylome and co-altered miRNA expression will be used to identify epigenetic modifications of high importance. We will test these hypotheses in three specific aims SPECIFIC AIM 1: Measure genome-wide epigenetic changes occurring at different stages of the HPV16 life cycle. SPECIFIC AIM 2: Measure genome-wide epigenetic changes occurring during HPV16 carcinogenic progression. SPECIFIC AIM 3: Delineate epigenetic modifications that occur in response to ART treatment.

 描述（由申请人提供）： 与HPV16感染相关的口咽癌的百分比从1984年至1989年的16.3%上升到2000年至2004年的71.7%。相比之下，与烟草相关的口咽癌的数量同期一直在稳步下降多个国家也报告了类似的变化，影响艾滋病毒感染者的癌症负担也发生了重大变化。美国在引入高效抗逆转录病毒治疗 (HAART) 的 12 年间，在这些新出现的恶性肿瘤中，HPV 相关的口腔/咽部癌症在 AIDS 诊断后显着增加，正在迅速改变癌症的格局。然而，我们对口腔 HPV 感染和致癌进展的机制和自然史知之甚少，对生殖道 HPV 相关致癌性的了解并不令人满意。 HPV 是侵袭性宫颈癌的必要原因，但不是其充分原因。甲基化的表观遗传标记是人类癌症的常见标志，使用适当的模型系统进行表观遗传研究可以显着增加我们对机制和信号传导的了解。驱动 HPV 感染、生命周期和肿瘤发生的途径，异常的 microRNA (miRNA) 表达被认为是 HPV 感染的角质形成细胞表达一组不同的 miRNA 的新的致癌机制。此外，与未感染的角质形成细胞相比，在非分化单层培养中生长的 HPV 感染的细胞表达一组不同的 miRNA，我们的长期目标是研究与 HPV 相关的口腔疾病的表观遗传机制。 90-95% 的 HNSCC 的研究重点是 HPV16。我们的假设是 HPV 生命周期的影响。 HIV 抗逆转录病毒治疗 (ART) 进一步影响口腔上皮表观基因组的致癌作用，对甲基化组和共同改变的 miRNA 表达的下一代测序分析将影响宿主基因组和病毒基因组的表观基因组。我们将在三个特定目标中测试这些假设。具体目标 1：测量 HPV16 生命周期不同阶段发生的全基因组表观遗传变化。具体目标 2：测量 HPV16 致癌进展过程中发生的全基因组表观遗传变化。具体目标 3：描述 ART 治疗引起的表观遗传修饰。