MicroRNA and Transcription Factor Co-regulation in Cancer

 描述(申请人提供)：最近的研究表明microRNAs(MiRNAs)在癌症发病机制中的关键作用，表明miRNAs可以作为癌症预后、诊断和治疗的生物标志物在临床上有用。到目前为止，由于数据的异质性和疾病的复杂性，癌症研究中的miRNA信息变化很大。在这一应用中，在目标1中，我们将开发新的统计方法来系统地对癌症基因组图谱(TCGA)项目报告的前四种癌症(胶质母细胞瘤、卵巢癌、结直肠癌和肺癌)中miRNA的表达进行荟萃分析。对于这些癌症中的每一种，已经报道了300多个调控失调的miRNAs，这使得这个目标不仅可行，而且迫在眉睫。在目标2中，我们将开发创新的策略，通过miRNA和转录因子(TF)共调控网络分析来探索miRNAs在癌症中的功能。对于每种癌症，我们将使用miRNA/mRNA共表达图谱和来自相应TCGA数据集的TF/基因调控来构建癌症特异性调控网络。然后，我们将确定反映癌症中miRNA和TF共同调节的网络模块。我们将研究四种癌症之间的共同调控模块和每种特定癌症的独特模块。在目标3中，我们将使用已有的组织和匹配的正常样本以及已建立的细胞系，在来自目标2的常见调控模块中对选定的miRNAs及其靶点进行实验验证。这项应用将是对前四种TCGA癌症中所有可用的miRNA研究的第一次系统研究。AIM 1的成功完成将为我们提供一份关于胶质母细胞瘤、卵巢癌、结直肠癌和肺癌的循证miRNAs清单；AIM 2的成功完成将为我们在调控网络水平上对这些癌症中miRNA和TF的共同调控提供全面的探索；AIM 3的成功完成将验证我们的元和网络方法，帮助我们了解miRNA的调控机制，并为我们提供潜在的治疗靶点。虽然这是一个相当探索性的项目，但由于文献和TCGA提供的大量数据，我们预计这个项目是高度可行和及时的。这项在复杂疾病中检测功能重要的miRNAs的开创性努力将极大地增强我们对癌症调控系统的理解，这可能会导致有效的预防、诊断和治疗策略的发展。

 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.