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MicroRNAs and other non-coding RNAs in Colorectal Metastasis

结直肠转移中的 MicroRNA 和其他非编码 RNA

基本信息

批准号：
7653452
负责人：
George A Calin
金额：
$ 33.5万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7653452
关键词：
Adenocarcinoma Apoptosis Bioinformatics Biological Biological Process Biology Cell Cycle Cell Proliferation Cells Cessation of life Code Colon Carcinoma Colorectal Colorectal Adenocarcinoma Colorectal Cancer Complex Computer Simulation Data Databases Disease Down-Regulation Expressed Sequence Tags Family Functional RNA Gene Family Gene Proteins Genes Genetic Transcription Goals Hereditary Disease Heterogeneity Human Investigation Malignant Neoplasms Messenger RNA MicroRNAs Microsatellite Repeats Molecular Abnormality Molecular Diagnosis Molecular Profiling Names Neoplasm Metastasis Patients Pharmacotherapy Process Proteins Research Role Suppressor Genes Testing Transcript Transfection Tumor Cell Invasion Tumor Suppressor Genes Uncertainty Untranslated RNA Upper arm base calin cancer cell chemotherapy colon cancer cell line gene therapy genome-wide in vitro Model in vivo metastatic colorectal metastatic process novel marker outcome forecast overexpression programs protein expression research study response tool tumorigenesis

项目摘要

For three decades, alterations of protein-coding oncogenes and tumor suppressors genes have been considered as the causes of tumorigenesis. Recent advances proved without doubts that cancer is a complex genetic disease involving structural and expression abnormalities of both coding and non-coding genes. We pioneered the idea that small non-coding RNAs (ncRNAs) named microRNAs (miRNAs) and other larger ncRNAs named ultraconserved genes are involved in human tumorigenesis and particularly in colorectal cancers (CRC). The pathogenetic mechanisms of the final steps of tumorigenesis, the metastases, is still largely unknown. The broad, long-term purposes of this application are to decipher the roles of ncRNAs during the metastatic process of CRC and to understand the ncRNAs genetic abnormalities in the set of patients that will represent the initial target of miRNA-based gene therapy. To achieve this, we will use a four-aimed strategy applied to a large panel of patients divided in two arms: one without and the other having metastases. First, based on microarray experiments with genome-wide miRNA and expressed sequence tags (ESTs) profiling and on bioinformatics studies, we will develop a large database of miRNAs, ultraconserved genes and large ncRNAs expression and correlate this with databases of expressed ESTs. Second, based on the negative correlations that we will found using bioinformatics tools, we will analyze the possible interactions between ncRNAs and messenger RNAs of protein coding genes significant for mestatases. Third, we will investigate the biological functions related to the metastasis process for some verry significantly differentially expressed miRNAs and UCGs by using in vitro models of colon cancer metastases. Based on our preliminary data, we will include as the top candidates for such studies miR-21, miR-192, miR-215, and miR-222, as well as the non-coding UCGs uc.160, uc.170A and uc.310, and the top three miRNAs and top three UCGs selected according to statistical criteria obtained from the patient study (if different from the previous genes). The final results of the described tasks will reveal new markers for molecular diagnosis and prognosis and new targets for drug therapy.

三十年来，蛋白质编码癌基因和肿瘤抑制基因的改变被认为是肿瘤发生的原因。最近的进展毫无疑问地证明，癌症是一种复杂的遗传疾病，涉及编码基因和非编码基因的结构和表达异常。我们率先提出了小的非编码rna (ncRNAs)，称为microRNAs （miRNAs）和其他更大的ncRNAs，称为超保守基因，参与人类肿瘤发生，特别是结肠直肠癌（CRC）。肿瘤发生的最后一步，即转移的发病机制在很大程度上仍是未知的。该应用的广泛和长期目的是破译ncRNAs在结直肠癌转移过程中的作用，并了解将代表mirna基因治疗初始目标的患者组中的ncRNAs遗传异常。为了实现这一目标，我们将采用一种四目标策略，将一组患者分为两组：一组没有转移，另一组有转移。首先，基于全基因组miRNA和表达序列标签（est）分析的微阵列实验和生物信息学研究，我们将建立一个大型miRNA、超保守基因和大型ncrna表达数据库，并将其与表达est数据库相关联。其次，基于我们将使用生物信息学工具发现的负相关，我们将分析ncrna和对转移有重要意义的蛋白质编码基因的信使rna之间可能的相互作用。第三，我们将通过体外结肠癌转移模型，研究一些差异表达非常显著的mirna和UCGs在转移过程中的生物学功能。根据我们的初步数据，我们将纳入miR-21、miR-192、miR-215和miR-222，以及非编码UCGs uc作为此类研究的首选候选。160年,加州大学。170A和uc。310，以及根据从患者研究中获得的统计标准选择的前三个mirna和前三个ucg（如果与前面的基因不同）。这些任务的最终结果将揭示分子诊断和预后的新标记以及药物治疗的新靶点。