Chlamydia & Aberrant DNA Methylation in Cervical Cancer

衣原体

• 批准号: 7425965
• 负责人: Nancy B. Kiviat
• 金额: $ 49.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-13 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425965
• 关键词: Aberrant DNA Methylation; Africa; Age; Carcinogens; Case-Control Studies; Cells; Cervical; Chlamydia; Chronic; Contraceptive Usage; CpG Islands; DNA; DNA Damage; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; Development; Down-Regulation; Epigenetic Process; Exposure to; Gene Activation; Gene Expression; Genes; Genetic Transcription; Genomics; Hemophilus ducreyi; Histone Deacetylase; Hour; Human; Human Herpesvirus 2; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Hypermethylation; In Vitro; Infection; Inflammation; Invasive; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Methylation; Molecular; Multiparity; Natural History; Neoplasms; Numbers; Oncogenic; Oral; Papillomavirus; Pathogenesis; Pattern; Phase; Promoter Regions; Public Health; RNA; Reactive Oxygen Species; Reporting; Research Personnel; Risk; Risk Factors; Sampling; Serological; Smoking; Squamous Cell; Time; Treponema pallidum; Week; Woman; base; cancer type; carcinogenesis; insight; non-oncogenic; novel; parity; pathogen

DESCRIPTION (provided by applicant): Infection with oncogenic human papillomaviruses (HPV) is necessary, but not sufficient, for development of ICC and exposure to other co-carcinogens is required for progression to malignancy. After adjusting for the presence of oncogenic HPV, multiple studies report C. trachomatis, a non-oncogenic, obligate intracellular pathogen is a risk factor for ICC. We hypothesize that C. trachomatis infection increases risk of malignancy as a result of inducing aberrant DNA methylation in the promoter region of a variety of genes, including some relevant to the pathogenesis of ICC. Aberrant DNA methylation, widely accepted as important in the pathogenesis of cancers, including ICC, is an epigenetic change associated with the abnormal silencing or activation of gene transcription, and we have previously identified 30 hypermethylated ICC associated genes. Support for our hypothesis includes: 1) C. trachomatis elicits prolonged chronic inflammation which produces high levels of reactive oxygen species, known to damage DNA and alter cellular methylation. 2) C. trachomatis is an obligate intracellular pathogen, which can establish persistent infection. In vitro studies have shown that, even in the absence of integration, intracellular pathogens alter patterns of cellular methylation. 3) A review of our recent in-vitro studies describing alterations of cellular gene transcription associated with C. trachomatis infection revealed that a substantial number of the 30 genes we have shown are aberrantly methylated in association with ICC were down regulated as a result of C. trachomatis infection [Preliminary Studies]. To determine whether C. trachomatis contributes to the pathogenesis of ICC by inducing aberrant DNA methylation, we are proposing a study based in West Africa, where cervical cancer is, and is likely to remain, a major public health problem. We hypothesize that a subset of our 30 ICC-associated hypermethylated genes will be associated with serologic evidence of C. trachomatis infection among women with, and without, ICC. Complementary in vitro studies in HPV 16 E6/E7 immortalized ectocervical cells will provide insights into the molecular basis and natural history of such changes. This study will provide information about the well established, but not well understood association between infection, inflammation, and cancer, and, may support the development of novel treatment approaches based on alteration of aberrant patterns of methylation, which in phase one trials appear promising.

描述(由申请人提供)：感染致癌性人乳头瘤病毒(HPV)是发展ICC的必要条件，但不是充分条件，而接触其他致癌物是癌变所必需的。在调整致癌HPV的存在后，多项研究报告沙眼衣原体是ICC的危险因素，沙眼衣原体是一种非致癌的专性细胞内病原体。我们假设沙眼衣原体感染会导致多种基因启动子区域的DNA甲基化异常，包括一些与ICC发病相关的基因，从而增加发生恶性病变的风险。DNA甲基化异常是一种与基因转录异常沉默或激活有关的表观遗传学改变，被广泛认为在包括ICC在内的癌症的发病机制中起重要作用，我们以前已经发现了30个与ICC相关的高甲基化基因。支持我们的假设包括：1)沙眼衣原体会引起长期的慢性炎症，产生高水平的活性氧物种，已知会破坏DNA并改变细胞甲基化。2)沙眼衣原体是一种专性的细胞内病原体，可建立持续感染。体外研究表明，即使在没有整合的情况下，细胞内的病原体也会改变细胞甲基化的模式。3)对我们最近描述与沙眼衣原体感染相关的细胞基因转录变化的体外研究的回顾表明，我们已经发现的与ICC相关的30个基因中有相当数量的异常甲基化下调是沙眼衣原体感染的结果[初步研究]。为了确定沙眼衣原体是否通过诱导异常的DNA甲基化而导致ICC的发病，我们提议在西非进行一项研究，那里的宫颈癌是并可能仍然是一个主要的公共卫生问题。我们假设，我们的30个ICC相关的高甲基化基因中的一个子集将与有和没有ICC的女性中沙眼衣原体感染的血清学证据有关。对HPV16E6/E7永生化宫颈外细胞的补充体外研究将为这种变化的分子基础和自然历史提供深入的见解。这项研究将提供关于感染、炎症和癌症之间已建立的、但尚未很好理解的联系的信息，并可能支持基于甲基化异常模式改变的新治疗方法的开发，这在第一阶段试验中似乎是有希望的。