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

 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在同一时期一直在稳步下降。据报道，许多国家也出现了类似的变化。在引入高效抗逆转录病毒疗法(HAART)的12年时间里，美国艾滋病毒感染者患癌症的负担发生了实质性变化。在这些新出现的恶性肿瘤中，HPV相关的口腔/咽部癌症在被诊断为艾滋病后显著增加。HPV正在迅速改变HNSCC的面貌。然而，口腔HPV感染和致癌进展的机制和自然历史却知之甚少。对生殖道HPV相关致癌性知识的外推并不能满足我们对口腔HPV疾病的理解。人乳头瘤病毒是浸润性宫颈癌的必要原因，但不是充分原因。甲基化的表观遗传标记是人类癌症的常见特征。使用合适的模型系统进行表观遗传学研究可以显著增加我们对驱动HPV感染、生命周期和肿瘤发生的机制和信号通路的了解。MicroRNAs(MiRNAs)的异常表达已被公认为一种新的致癌分子机制。与未感染的角质形成细胞相比，HPV感染的角质形成细胞表达一组不同的miRNAs。此外，在非分化单层培养中生长的HPV感染细胞与HPV感染的分化角质形成细胞相比，表达一组不同的miRNAs。我们的长期目标是研究HPV相关口腔疾病的表观遗传学机制。HPV16与90-95%的HNSCC有关。我们的研究将集中在HPV16上。我们的假设是，HPV生命周期和致癌对口腔上皮表观基因组景观的影响进一步受到艾滋病毒抗逆转录病毒治疗(ART)的影响。宿主基因组和病毒基因组的表观基因组都会受到影响。甲基组的下一代测序分析和共同改变的miRNA表达将被用来识别高度重要的表观遗传修饰。我们将在三个特定的目标中测试这些假设，具体目标1：测量在HPV16生命周期的不同阶段发生的全基因组表观遗传变化。特定目的2：测量在HPV16致癌进展过程中发生的全基因组表观遗传学变化。具体目的3：描述抗逆转录病毒治疗后发生的表观遗传修饰。

 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.