Epigentic Alterations in Pre-malignant Tissue of the Bladder

膀胱癌前组织的表观改变

• 批准号: 8107499
• 负责人: Gangning Liang
• 金额: $ 26.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107499
• 关键词: Aberrant DNA Methylation; Address; Age; Aging; Apoptosis; Area; Beryllium; Biological; Biological Assay; Biological Markers; Bladder; Bladder Neoplasm; Bladder Tissue; Bladder Urothelial Cell; Cancer Patient; Cancer cell line; Cell Line; Cells; Cessation of life; Clinical; CpG Islands; DNA; DNA Methylation; Development; Diagnosis; Disease; Ectopic Expression; Epigenetic Process; Epithelial Cells; Epithelium; Excision; Gene Expression; Health; Hypermethylation; Institutes; L1 Elements; Laboratories; Left; Link; MET Oncogene; MET gene; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediator of activation protein; Methylation; Molecular; Monitoring for Recurrence; Normal tissue morphology; Oncogene Activation; Oncogenes; Operative Surgical Procedures; Outcome; Paper; Patients; Premalignant; Premalignant Change; Proto-Oncogenes; PubMed; RNA Interference; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; Role; Scientist; Site; Staging; Time; Transcript; Transitional Cell Carcinoma; Translating; Transurethral Resection; Tumor Cell Invasion; Tumor Suppressor Genes; United States; Urine; Visit; Woman; cancer cell; cancer diagnosis; cell growth; follow-up; healthy volunteer; high risk; men; promoter; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Bladder cancer is the fifth most common cancer in the United States. Although these tumors can be removed by transurethral resection, about 50-80% will recur. Since recurrence is a common feature of superficial bladder cancer, it is often thought that this may be due to pre malignant changes in the bladder, although it has not been well defined molecularly. Aberrant DNA methylation has been proposed as an attractive candidate for the underlying alterations governing pre malignant changes. Hypomethylation of LINE-1 retrotransposable elements is quite common in many cancers including bladder cancer. We recently found hypomethylation of a specific LINE-1 element in bladder cancer cells that was also present in the corresponding normal appearing cells regardless of the distance from the site of the tumor. This particular LINE-1 element (MET-LINE) is located in the intronic region of the proto- oncogene MET and we have detected the expression of a truncated form of the oncogene in cells with hypomethylated promoter of MET-LINE. These results may indicate pre malignant changes in the bladder where there is a reduction of methylation of a specific LINE 1 and an increased likelihood of expression of an oncogene. In this proposal, we plan first to further investigate the correlation between hypomethylation of the specific LINE-1 and ectopic expression of truncated MET as one of mediators of pre milignant changes by the Pyrosequencing assay and real time RT-PCR to measure DNA methylation and gene expression; second to detect methylation changes of the MET-LINE in urine sediments of patients before and after surgical excision to study the potential role of hypomethylation of the MET-LINE as a marker of recurrence by a highly sensitive assay (MethyLight); and finally, to characterize the role of truncated MET during tumorigenesis. Accomplishment of these specific aims will allow us to obtain evidence of premalignant changes at the molecular level in bladder epithelial cells from bladder cancer patients without evidence of malignancy and address the potential mechanism of highly recurrent bladder cancers. Finally this translational project will bring together basic scientists and clinicians to translate clinical findings into laboratory questions and use these fundamental discoveries to better the lives of patients with this disease. PUBLIC HEALTH RELEVANCE: In the United States, bladder cancer is the fourth most common cancer diagnosis in men and the eighth most common in women with 50-80% of cases recurring, in 2007 there were 67160 new cases and 13750 deaths according to the Natinal Cancer Institute. Accomplishment of this proposal will allow us to elucidate the potential cause of the frequent recurrence of bladder cancer and develop a highly specific and sensitive biomarker not only for diagnosis of bladder cancer but also for monitoring the recurrence of bladder cancer.

描述（由申请人提供）：膀胱癌是美国第五大最常见的癌症。尽管这些肿瘤可以通过尿道切除去除，但大约50-80％会复发。由于复发是表面膀胱癌的常见特征，因此通常认为这可能是由于膀胱前的恶性变化所致，尽管它尚未得到很好的分子定义。已经提出异常的DNA甲基化作为管理前恶性变化的潜在改变的有吸引力的候选者。在包括膀胱癌在内的许多癌症中，线路1逆转录元素的低甲基化非常普遍。我们最近发现，无论距肿瘤部位的距离如何，膀胱癌细胞中特定的线1元素的低甲基化也存在于相应的正常出现细胞中。该特定的LINE-1元素（MET-LINE）位于原始癌基因的内含子区域中，我们检测到具有Met-Line的低甲基化启动子的细胞中癌基因的截短形式的表达。这些结果可能表明膀胱的恶性变化在特定线1的甲基化降低，并且表达癌基因表达的可能性增加。在该提案中，我们首先计划进一步研究特定线1的低甲基化与截短的异位表达之间的相关性，作为通过焦磷酸化测定法和实时RT-PCR测量DNA甲基化和基因表达的实时RT-PCR，作为前内加性变化的介体之一。其次要检测手术切除前后患者尿液沉积物中METLINE的甲基化变化，以研究METLINE通过高度敏感测定法（Methylight）作为复发标志的Met-Line作为复发标志的潜在作用（Methylight）；最后，要表征在肿瘤发生过程中截短的MET的作用。这些特定目标的实现将使我们能够获得来自膀胱癌患者膀胱上皮细胞的分子水平上发生前变化的证据，而没有恶性证据并解决了高度复发性膀胱癌的潜在机制。最后，这个转化项目将汇集基础科学家和临床医生，将临床发现转化为实验室问题，并利用这些基本发现来改善这种疾病患者的生活。公共卫生相关性：在美国，膀胱癌是男性中第四个最常见的癌症诊断，也是50-80％的女性中最常见的第八例诊断，在2007年，根据Natinal Cancer Institute，2007年有67160例新病例和13750例死亡。该提案的完成将使我们能够阐明膀胱癌频繁复发的潜在原因，并开发出高度特异性和敏感的生物标志物，不仅用于诊断膀胱癌的诊断，还用于监测膀胱癌的复发。