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）：具有致癌性人乳头瘤病毒（HPV）的感染是必要的，但不足以开发ICC并暴露于其他共霉素才能发展为恶性肿瘤。在调整了致癌性HPV的存在之后，多项研究报告说，沙眼曲霉（一种非核，强性的细胞内病原体是ICC的危险因素。我们假设，沙眼梭状芽胞盘感染增加了由于在多种基因的启动子区域诱导异常DNA甲基化而增加了恶性肿瘤的风险，包括与ICC的发病机理有关的一些。在包括ICC在内的癌症的发病机理中广泛接受的异常DNA甲基化是与异常的沉默或基因转录激活相关的表观遗传变化，我们先前已经鉴定出30个高甲基化ICC相关的基因。对我们的假设的支持包括：1）梭状芽孢杆菌引起延长慢性炎症，该慢性炎症会产生高水平的活性氧，已知会损害DNA并改变细胞甲基化。 2）沙眼梭状芽孢杆菌是一种强大的细胞内病原体，可以建立持续的感染。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）对我们最近的体外研究的综述，描述了与沙眼炎感染相关的细胞基因转录的改变，表明我们所显示的30个基因中有大量与ICC相关的甲基甲基化受到异常的甲基化受到调节，该甲基受到调节。为了确定沙aratomis是否通过诱导异常的DNA甲基化来促进ICC的发病机理，我们提出了一项基于宫颈癌的西非研究，并且可能仍然是主要的公共卫生问题。我们假设30个与ICC相关的高甲基化基因的子集将与具有ICC和没有ICC的妇女中的沙眼曲霉感染的血清学证据有关。 HPV 16 E6/E7的体外研究互补的内宫颈细胞将提供有关这种变化的分子基础和自然历史的见解。这项研究将提供有关感染，炎症和癌症之间建立良好但尚不清楚的关联的信息，并可能支持基于异常甲基化模式的改变的新型治疗方法的发展，在第一阶段试验中，这似乎很有希望。