Chlamydia & Aberrant DNA Methylation in Cervical Cancer

描述（由申请人提供）：致瘤性人乳头瘤病毒（HPV）感染对于ICC的发展是必要的，但不是充分的，暴露于其他共致癌物对于恶性肿瘤的进展是必需的。在校正了致癌性HPV的存在后，多项研究报告沙眼衣原体，一种非致癌性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增加恶性肿瘤的风险是由于在多种基因的启动子区域诱导异常DNA甲基化，包括一些与ICC发病机制相关的基因。异常DNA甲基化是一种与基因转录异常沉默或激活相关的表观遗传变化，在包括ICC在内的癌症发病机制中被广泛认为是重要的，我们之前已经发现了30个高甲基化的ICC相关基因。支持我们的假设包括：1)沙眼衣原体引起长时间的慢性炎症，产生高水平的活性氧，已知会破坏DNA并改变细胞甲基化。2)沙眼衣原体是专性细胞内病原体，可建立持续性感染。体外研究表明，即使在没有整合的情况下，细胞内病原体也会改变细胞甲基化的模式。3)我们最近对与沙眼衣原体感染相关的细胞基因转录改变的体外研究进行了回顾，结果显示，我们发现的与ICC相关的30个基因中，有相当数量的基因在沙眼衣原体感染后异常甲基化而下调[初步研究]。为了确定沙眼原体是否通过诱导异常DNA甲基化来促进ICC的发病机制，我们提议在西非进行一项研究，在那里，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，我们的30个ICC相关的高甲基化基因中的一个子集将与患有或不患有ICC的女性中沙眼衣原体感染的血清学证据相关。对HPV 16 E6/E7永生化外宫颈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见解。该研究将提供关于感染、炎症和癌症之间已建立但尚未完全理解的关联的信息，并可能支持基于甲基化异常模式改变的新型治疗方法的发展，这在一期试验中看起来很有希望。

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.