Chlamydia & Aberrant DNA Methylation in Cervical Cancer

衣原体

• 批准号: 7630390
• 负责人: Nancy B. Kiviat
• 金额: $ 49.03万
• 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/7630390
• 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 Expression; Genes; Genetic Transcription; Genomics; Hemophilus ducreyi; Histone Deacetylase; Hour; Human Herpesvirus 2; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Hypermethylation; In Vitro; Infection; Inflammation; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Methylation; Molecular; Multiparity; Natural History; Neoplasms; Oncogenic; Oral Contraceptives; 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; 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）：致癌人乳头瘤病毒 (HPV) 感染对于 ICC 的发展是必要的，但还不够，并且需要接触其他共致癌物才能进展为恶性肿瘤。在调整致癌 HPV 的存在后，多项研究报告沙眼衣原体（一种非致癌的专性细胞内病原体）是 ICC 的危险因素。我们假设沙眼衣原体感染会在多种基因（包括一些与 ICC 发病机制相关的基因）启动子区域诱导异常 DNA 甲基化，从而增加恶性肿瘤的风险。异常 DNA 甲基化被广泛认为在癌症（包括 ICC）的发病机制中很重要，是一种与基因转录异常沉默或激活相关的表观遗传变化，我们之前已经鉴定了 30 个高甲基化的 ICC 相关基因。支持我们假设的包括：1) 沙眼衣原体引起长期慢性炎症，产生高水平的活性氧，已知会损害 DNA 并改变细胞甲基化。 2) 沙眼衣原体是一种专性细胞内病原体，可建立持续感染。体外研究表明，即使没有整合，细胞内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改变的体外研究的回顾表明，我们已经证明与 ICC 相关的 30 个基因异常甲基化中的大量基因因沙眼衣原体感染而下调[初步研究]。为了确定沙眼衣原体是否通过诱导异常 DNA 甲基化而导致 ICC 的发病，我们提议在西非进行一项研究，在西非，宫颈癌是并且很可能仍然是一个主要的公共卫生问题。我们假设 30 个 ICC 相关高甲基化基因的一个子集将与患有和不患有 ICC 的女性沙眼衣原体感染的血清学证据相关。对 HPV 16 E6/E7 永生化宫颈外细胞的补充体外研究将为了解此类变化的分子基础和自然史提供见解。这项研究将提供有关感染、炎症和癌症之间已确定但尚未充分理解的关联的信息，并且可能支持基于改变异常甲基化模式的新治疗方法的开发，这在第一阶段试验中似乎很有希望。