Non-coding RNAs as Prognostic and Diagnostic Markers in Prostate Cancer

非编码 RNA 作为前列腺癌的预后和诊断标志物

• 批准号: 7733306
• 负责人: Stefan Ambs
• 金额: $ 22.43万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733306
• 关键词: African American; American; Androgens; Area; Baltimore; Blood; Blood specimen; Cancer Detection; Cancer Patient; Cancerous; Class; Code; Collaborations; Cultured Cells; Data; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Doctor of Medicine; E2F1 gene; Elements; Ethnic Origin; European; Extraprostatic; Functional RNA; Gene Expression Profiling; Gene Targeting; Genes; Genetic Transcription; Genome; Genomics; Gleason Grade for Prostate Cancer; Goals; Homologous Gene; Human; Human Genome; Introns; Link; MCM7 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Maryland; Messenger RNA; MicroRNAs; Molecular Profiling; Normal tissue morphology; Numbers; Ohio; Oncogenic; Organ; Patients; Pilot Projects; Population; Process; Prognostic Marker; Property; Prostate; Prostatic Neoplasms; Proteins; Publications; Race; Rattus; Relative (related person); Reporting; Role; Sampling; Sampling Studies; Serum; Solid; Techniques; Technology; Time; Tissues; Transcript; Tumor Suppressor Genes; Universities; base; cancer cell; case control; human protein tyrosine kinase brk; mouse genome; oncoprotein p21; outcome forecast; prognostic; protein expression; size; tumor

MicroRNA expression is commonly altered in solid human tumors. Multiple microRNAs have been shown to have oncogenic properties, or act like tumor suppressor genes. These microRNAs have been termed oncomiRs. An alteration in their expression is causatively linked to cancer development and can predict disease outcome. Recently, the Croce group (Carlo Croce, M.D., Ohio State University) reported that expression of RNAs encoded by ultraconserved genomic regions (ucRNA) is altered in human cancer. At this time, 481 of these ultraconserved elements have been annotated and defined as segments greater than 200 bp with perfect conservation among human, rat, and, mouse genomes. In collaboration with Dr. Croce, we are investigating microRNA and ucRNA expression profiles of prostate tumors. This teamwork led to the first study that applied large-scale gene expression profiling to identify alterations in microRNA function in tumors from African-American and European-American patients. We determined genome-wide expression of microRNAs and mRNAs in 60 primary prostate tumors and 16 non-tumor prostate tissues. The mRNA analysis revealed that key components of microRNA processing and several microRNA host genes, e.g., MCM7 and C9orf5, were significantly up-regulated in prostate tumors. Consistent with these findings, tumors expressed the miR-106b-25 cluster, which maps to intron 13 of MCM7, and miR-32, which maps to intron 14 of C9orf5, at significantly higher levels than non-tumor prostate. The expression levels of other microRNAs, including a number of miR-106b-25 cluster homologues, were also altered in prostate tumors. Additional differences in microRNA abundance were found between organ-confined tumors and those with extraprostatic disease extension. Lastly, we found evidence that some microRNAs are androgen-responsive and that tumor microRNAs influence transcript abundance of protein-coding target genes in the cancerous prostate. In cell culture, E2F1 and p21/WAF1 were identified as targets of miR-106b, Bim of miR-32, and exportin-6 and protein tyrosine kinase 9 of miR-1. In summary, microRNA expression becomes altered with the development and progression of prostate cancer. Some of these microRNAs regulate the expression of cancer-related genes in prostate cancer cells. We also compared the tumor microRNA signatures between African-Americans and European-Americans, but only a few microRNAs were differentially expressed. miR-129, miR-196b, and miR-342 were found to be less abundant in tumors of African-Americans than in tumors of European-Americans. From the analysis, it did not appear that tumor microRNAs are differentially expressed to any major degree by race/ethnicity. Currently, we are analyzing the expression profiles for ucRNA in these samples. Preliminary results indicate that numerous ucRNAs are differentially expressed between tumor and surrounding normal tissue, by Gleason grade, and between organ-confined tumors and those with extraprostatic disease extension. The chip data are in the process of being validated by other methods. A recent publication (Proc Natl Acad Sci USA 105:10513-18, 2008) found that circulating microRNAs, which are only 17-25 bp in size, are stable blood-based markers that could be useful for cancer detection. We have begun evaluating the technology for analyzing microRNA abundance in serum samples from prostate cancer cases and controls to examine whether the microRNA expression profile of blood samples can be used to predict the presence of tumor. In a pilot study, we will evaluate the relative abundance of several candidate microRNAs in serum samples from cancer patients and population-based controls. These microRNAs will be selected from the tumor microRNA expression profile that we identified. Samples for the study will be drawn from our ongoing case-control of prostate cancer in the greater Baltimore, Maryland area.

在人类固体肿瘤中，microRNA表达通常会改变。已显示多个microRNA具有致癌特性，或者像肿瘤抑制基因一样起作用。这些microRNA被称为oncomirs。它们表达的改变与癌症的发展有关，可以预测疾病的结果。最近，Croce集团（Carlo Croce，M.D。，俄亥俄州立大学）报告说，由超保存的基因组区域（UCRNA）编码的RNA在人类癌症中改变了。目前，已将481个超保守的元素注释并定义为大于200 bp的段，在人，大鼠和小鼠基因组中具有完美的保护。与Croce博士合作，我们正在研究前列腺肿瘤的microRNA和UCRNA表达谱。这项团队合作导致了第一项应用大规模基因表达分析的研究，以确定非裔美国人和欧美患者肿瘤中microRNA功能的变化。我们确定了60个原发性前列腺肿瘤和16个非肿瘤前列腺组织中microRNA和mRNA的全基因组表达。 mRNA分析表明，在前列腺肿瘤中，microRNA加工和几种microRNA宿主基因（例如MCM7和C9ORF5）的关键成分显着上调。与这些发现一致，肿瘤表达了miR-106b-25簇，该簇映射到MCM7的内含子13和miR-32，其映射到C9orf5的内含子14的水平高于非肿瘤前列腺。前列腺肿瘤中也改变了其他microRNA的表达水平，包括许多miR-106b-25簇同源物。 在器官肿瘤和具有胸腔外疾病扩展的肿瘤之间发现了microRNA丰度的其他差异。最后，我们发现一些证据表明某些microRNA具有雄激素响应性，并且肿瘤microRNA会影响癌性前列腺中蛋白质编码靶基因的转录物丰度。在细胞培养中，E2F1和P21/WAF1被鉴定为miR-1的miR-106b，miR-32的miR-106b，miR-32和Exportin-6和蛋白酪氨酸激酶9。总之，随着前列腺癌的发展和发展，microRNA表达会改变。这些microRNA中的一些调节前列腺癌细胞中癌症相关基因的表达。我们还比较了非裔美国人和欧美人之间的肿瘤microRNA特征，但只有少数microRNA被差异表达。发现非裔美国人肿瘤中的miR-129，miR-196b和miR-342在欧洲裔美国人的肿瘤中的丰富。从分析中，似乎没有通过种族/种族在任何重要程度上差异地表达肿瘤microRNA。当前，我们正在分析这些样品中UCRNA的表达曲线。初步结果表明，通过肿瘤和周围的正常组织，Gleason等级以及器官构造的肿瘤和具有压皮外疾病外疾病的肿瘤之间的肿瘤和周围正常组织之间差异表达。芯片数据正在通过其他方法验证。最近的出版物（Proc Natl Acad Sci USA 105：10513-18，2008）发现，只有17-25 bp的循环microRNA是稳定的基于血液的标记物，可用于癌症检测。我们已经开始评估该技术，用于分析来自前列腺癌病例和对照组中血清样品中的microRNA丰度，以检查是否可以使用血液样本的microRNA表达谱图来预测肿瘤的存在。在一项试点研究中，我们将评估来自癌症患者和基于人群对照的血清样品中几个候选microRNA的相对丰度。这些microRNA将从我们确定​​的肿瘤microRNA表达谱中选择。这项研究的样本将从我们正在进行的病例对照的前列腺癌对照中，在马里兰州大巴尔的摩地区。