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.

MicroRNA 表达在人类实体瘤中通常会发生改变。多种 microRNA 已被证明具有致癌特性，或者像肿瘤抑制基因一样发挥作用。这些 microRNA 被称为 oncomiR。它们表达的改变与癌症的发展存在因果关系，并且可以预测疾病的结果。最近，Croce 小组（俄亥俄州立大学医学博士 Carlo Croce）报告称，由超保守基因组区域 (ucRNA) 编码的 RNA 的表达在人类癌症中发生了改变。目前，其中 481 个超保守元件已被注释并定义为大于 200 bp 的片段，在人类、大鼠和小鼠基因组中具有完美的保守性。我们与 Croce 博士合作，正在研究前列腺肿瘤的 microRNA 和 ucRNA 表达谱。这项团队合作促成了第一项应用大规模基因表达谱分析来识别非裔美国人和欧洲裔美国患者肿瘤中 microRNA 功能变化的研究。我们测定了 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 分析显示，microRNA 加工的关键成分和几个 microRNA 宿主基因（例如 MCM7 和 C9orf5）在前列腺肿瘤中显着上调。与这些发现一致，肿瘤表达 miR-106b-25 簇（映射到 MCM7 的内含子 13）和 miR-32（映射到 C9orf5 的内含子 14），其水平显着高于非肿瘤前列腺。其他 microRNA（包括许多 miR-106b-25 簇同源物）的表达水平在前列腺肿瘤中也发生了改变。 在器官局限性肿瘤和前列腺外疾病扩展的肿瘤之间还发现了 microRNA 丰度的额外差异。最后，我们发现证据表明一些 microRNA 具有雄激素反应性，并且肿瘤 microRNA 影响癌性前列腺中蛋白质编码靶基因的转录丰度。在细胞培养中，E2F1 和 p21/WAF1 被确定为 miR-106b、miR-32 的 Bim 以及 miR-1 的输出蛋白 6 和蛋白酪氨酸激酶 9 的靶标。总之，microRNA 表达随着前列腺癌的发生和进展而改变。其中一些 microRNA 调节前列腺癌细胞中癌症相关基因的表达。我们还比较了非洲裔美国人和欧洲裔美国人之间的肿瘤 microRNA 特征，但只有少数 microRNA 存在差异表达。研究发现，非洲裔美国人肿瘤中的 miR-129、miR-196b 和 miR-342 含量低于欧洲裔美国人肿瘤中的含量。从分析来看，肿瘤 microRNA 的表达似乎没有因种族/民族而出现任何重大程度的差异。目前，我们正在分析这些样本中 ucRNA 的表达谱。初步结果表明，根据格里森分级，许多ucRNA在肿瘤和周围正常组织之间以及器官局限性肿瘤和前列腺外疾病扩展的肿瘤之间存在差异表达。芯片数据正在通过其他方法进行验证。最近的一篇出版物（Proc Natl Acad Sci USA 105:10513-18, 2008）发现，大小仅为 17-25 bp 的循环 microRNA 是稳定的血液标记物，可用于癌症检测。我们已经开始评估用于分析前列腺癌病例和对照血清样本中 microRNA 丰度的技术，以检查血液样本的 microRNA 表达谱是否可用于预测肿瘤的存在。在一项试点研究中，我们将评估癌症患者和基于人群的对照血清样本中几种候选 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。该研究的样本将从马里兰州大巴尔的摩地区正在进行的前列腺癌病例对照中抽取。