MicroRNA and Transcription Factor Co-regulation in Cancer

癌症中的 MicroRNA 和转录因子共同调控

• 批准号: 9093087
• 负责人: Zhongming Zhao
• 金额: $ 16.75万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-09 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093087
• 关键词: Biological; Biological Markers; Cancer Prognosis; Clinical; Colon; Colorectal Cancer; Complex; Data; Data Set; Development; Diagnosis; Disease; Ethnic Origin; Freezing; Gender; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Glioblastoma; Investigation; Knowledge; Lead; Literature; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Messenger RNA; Meta-Analysis; MicroRNAs; Modeling; Molecular Profiling; National Human Genome Research Institute; Normal tissue morphology; Oncogenes; Output; Pathogenesis; Pathway Analysis; Patients; Pilot Projects; Prevention; Procedures; Property; Publishing; Regulation; Regulator Genes; Reporting; Role; Sampling; Seeds; Statistical Methods; System; The Cancer Genome Atlas; Therapeutic; Tissues; Tumor Suppressor Proteins; Validation; cancer cell; cancer diagnosis; cancer subtypes; cancer type; cell type; cohort; computer framework; disease heterogeneity; established cell line; evidence base; genome-wide; innovation; insight; novel; outcome forecast; public health relevance; research study; success; therapeutic target; tool; transcription factor; transcriptome; transcriptomics; treatment response; treatment strategy; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Recent studies have implicated the critical roles of microRNAs (miRNAs) in the pathogenesis of cancer, suggesting that miRNAs can be clinically useful as biomarkers for cancer prognosis, diagnosis and treatment. To date, the miRNA information in cancer studies has varied greatly due to data heterogeneity and disease complexity. In this application, in Aim 1, we will develop novel statistical methods to systematically perform meta- analysis of miRNA expression in the first four cancers (glioblastoma, ovarian cancer, colorectal cancer, and lung cancer) reported by The Cancer Genome Atlas (TCGA) project. For each of these cancers, more than 300 dysregulated miRNAs have been reported, which makes this aim not only feasible but immediately needed. In Aim 2, we will develop innovative strategies to explore miRNAs' functions in cancer through miRNA and transcription factor (TF) co-regulatory network analysis. For each cancer, we will build cancer-specific regulatory networks using miRNA/mRNA co-expression profiling and TF/gene regulation derived from the corresponding TCGA dataset. We will then identify network modules that reflect miRNA and TF co-regulation in cancer. We will investigate both common regulatory modules among four types of cancer and unique modules for each specific cancer. In Aim 3, we will experimentally validate selected miRNAs and their targets in common regulatory modules from Aim 2 using already available tissue and matched normal samples as well as established cell lines. This application will be the first systematic investigation of all available miRNA studes in the first four TCGA cancers. The successful completion of Aim 1 will provide us with a list of evidence-based miRNAs in glioblastoma, ovarian cancer, colorectal cancer, and lung cancer; the successful completion of Aim 2 will provide us with a comprehensive exploration of miRNA and TF co-regulation at the regulatory network level in these cancers; the successful completion of Aim 3 will validate our meta- and network- approaches, help us understand the miRNA regulatory mechanisms, and provide us with potential therapeutic targets in these cancers. Although quite exploratory, we expect this project is highly feasible and timely due to the large amount of data available in literature and from TCGA. This pioneering effort to detect functionally important miRNAs in complex diseases will greatly enhance our understanding of the regulatory systems in cancer, which will likely lead to the development of effective prevention, diagnosis, and treatment strategies.

 描述（由申请人提供）：最近的研究表明 microRNA (miRNA) 在癌症发病机制中的关键作用，表明 miRNA 可在临床上用作癌症预后、诊断和治疗的生物标志物。由于数据异质性和疾病复杂性，研究存在很大差异。在本应用的目标 1 中，我们将开发新的统计方法，系统地对前四种癌症中的 miRNA 表达进行荟萃分析。癌症基因组图谱 (TCGA) 项目报告称，对于这些癌症（胶质母细胞瘤、卵巢癌、结直肠癌和肺癌），已报告了 300 多种失调的 miRNA，这使得这一目标不仅可行，而且是迫切需要的。在目标 2 中，我们将制定创新策略，通过 miRNA 和转录因子 (TF) 共调控网络分析来探索 miRNA 在癌症中的功能。对于每种癌症，我们将使用构建癌症特异性调控网络。来自相应 TCGA 数据集的 miRNA/mRNA 共表达分析和 TF/基因调控 然后，我们将识别反映癌症中 miRNA 和 TF 共调控的网络模块。在目标 3 中，我们将使用现有的组织和正常样本以及已建立的匹配细胞系，通过实验验证目标 2 中选定的 miRNA 及其目标。全部可用目标 1 的成功完成将为我们提供胶质母细胞瘤、卵巢癌、结直肠癌和肺癌中基于证据的 miRNA 列表；目标 2 的成功完成将为我们提供在这些癌症的调控网络水平上全面探索 miRNA 和 TF 的共同调控；目标 3 的成功完成将验证我们的元方法和网络方法，帮助我们了解 miRNA 的调控机制，以及尽管具有相当的探索性，但由于文献和 TCGA 提供的大量数据，我们预计该项目具有高度的可行性和及时性，这项在复杂疾病中检测功能重要的 miRNA 的开创性努力将极大地发挥作用。增强我们对癌症调节系统的了解，这可能会导致有效的预防、诊断和治疗策略的制定。