Micro RNA Profiling in Pediatric Cancers

儿科癌症中的 Micro RNA 分析

• 批准号: 7965928
• 负责人: Javed Khan
• 金额: $ 12.98万
• 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/7965928
• 关键词: 3' Untranslated Regions; Algorithms; Animals; Apoptosis; Binding; Biological Markers; Cell Line; Cells; Childhood; Development; Diagnosis; Embryonic Development; Exhibits; Functional RNA; Gene Expression; Genes; Genomics; Housing; Human; Machine Learning; Malignant Childhood Neoplasm; Malignant Neoplasms; Metabolism; MicroRNAs; Molecular Profiling; Neuroblastoma; Pathogenesis; Pediatric Neoplasm; Plant Genome; Pre-Clinical Model; Preclinical Drug Evaluation; Process; Prognostic Marker; Regulation; Reporting; Role; Sampling; Screening procedure; Tissues; Translational Repression; Validation; cancer type; cell growth; mRNA Expression; mRNA Transcript Degradation; outcome forecast; tumor; tumor xenograft; tumorigenic

1. Identify microRNA profiles that are good biomarkers of pediatric cancers. 2. Identify microRNA that are biomarkers for predicting prognosis. 3. Identify genomic context of microRNA expression, and how they correlate with mRNA expression 4. Identify miRNAs in genomically altered regions that control critical genes in neuroblastoma. 5. Functional validation of selected miRNAs 6. Mutational screening of microRNAs MicroRNAs are recently discovered small, non-coding RNA molecules encoded in the genomes of plants and animals. These highly conserved, 21-mer RNAs regulate the expression of genes by binding to their 3'-untranslated regions (3'-UTR) of specific mRNAs, causing translational inhibition or mRNA degradation. As many mRNAs may share this short sequence, microRNAs are capable of simultaneously influence the expression of a large set of genes. It is estimated that each microRNA can target hundreds of genes, and multiple microRNAs can target a single gene. So far 710 microRNAs (version 11.0) have been reported to be expressed in human cells (http://microrna.sanger.ac.uk/). Due to their regulatory roles in gene expression, there is increasing evidence that microRNAs are directly involved not only in normal embryogenesis, metabolism, cell growth, differentiation, and apoptosis, but also in pathogenesis of human cancers. Because most pediatric malignancies are developmental tumors, i.e., they arise from aberrant differentiation, we hypothesized that pediatric tumors will exhibit cancer and tissue specific microRNA expression profiles that may be associated with development and the tumorigenic process, which can be used in diagnosis and prognosis. In this study we investigate the expression profiles of microRNAs for a panel of pediatric cell lines and tumor xenografts for which mRNAs profiles were, and which are currently used as pediatric pre-clinical models for drug screening. Using this panel of samples representing 10 different types of pediatric tumors we explore if pediatric tumors differentially express microRNAs according to their diagnosis by performing microRNA profiling on in-house microRNA arrays. We use machine learning algorithm and statistical to identify microRNAs that can potentially be used as biomarkers for these cancer types. We will validate these findings on independent NB and RMS tumor samples. In addition, we explore the degree of co-regulation of the microRNAs with the host gene within which they are located. We are also investigate key microRNAs that are biologically relevant and can be used as prognostic markers in RMS.

1. 识别作为儿科癌症良好生物标志物的 microRNA 谱。 2. 识别作为预测预后的生物标志物的 microRNA。 3. 识别 microRNA 表达的基因组背景，以及它们如何与 mRNA 表达相关 4. 识别控制神经母细胞瘤中关键基因的基因组改变区域中的 miRNA。 5. 选定 miRNA 的功能验证 6. microRNA 的突变筛选 MicroRNA 是最近发现的在植物和动物基因组中编码的小型非编码 RNA 分子。这些高度保守的 21 聚体 RNA 通过与特定 mRNA 的 3'-非翻译区 (3'-UTR) 结合来调节基因的表达，从而引起翻译抑制或 mRNA 降解。由于许多 mRNA 可能共享这个短序列，因此 microRNA 能够同时影响大量基因的表达。据估计，每个microRNA可以靶向数百个基因，多个microRNA可以靶向单个基因。迄今为止，据报道有 710 个 microRNA（11.0 版）在人类细胞中表达（http://microrna.sanger.ac.uk/）。由于它们在基因表达中的调节作用，越来越多的证据表明，microRNA不仅直接参与正常胚胎发生、代谢、细胞生长、分化和凋亡，而且还参与人类癌症的发病机制。由于大多数儿科恶性肿瘤是发育性肿瘤，即它们由异常分化引起，因此我们假设儿科肿瘤将表现出癌症和组织特异性的 microRNA 表达谱，这些表达谱可能与发育和致瘤过程相关，可用于诊断和预后。在这项研究中，我们研究了一组儿科细胞系和肿瘤异种移植物的 microRNA 表达谱，其中 mRNA 谱是这些细胞系和肿瘤异种移植物的表达谱，目前这些细胞系和肿瘤异种移植物被用作儿科药物筛选的临床前模型。使用这组代表 10 种不同类型儿科肿瘤的样本，我们通过在内部 microRNA 阵列上进行 microRNA 分析，探索儿科肿瘤是否根据其诊断差异表达 microRNA。我们使用机器学习算法和统计来识别可用作这些癌症类型生物标志物的 microRNA。我们将在独立的 NB 和 RMS 肿瘤样本上验证这些发现。此外，我们还探索了 microRNA 与其所在宿主基因的共同调控程度。我们还研究了具有生物学相关性并可用作 RMS 预后标志物的关键 microRNA。