MicroRNA and Transcription Factor Co-regulation in Cancer

 描述（由申请人提供）：最近的研究已经暗示了微小RNA（miRNA）在癌症发病机制中的关键作用，表明miRNA可以在临床上用作癌症预后、诊断和治疗的生物标志物。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。在本申请中，在目的1中，我们将开发新的统计方法来系统地进行癌症基因组图谱（TCGA）项目报道的前四种癌症（胶质母细胞瘤、卵巢癌、结直肠癌和肺癌）中miRNA表达的Meta分析。对于这些癌症中的每一种，已经报道了超过300种失调的miRNA，这使得这一目标不仅可行，而且迫切需要。在目标2中，我们将开发创新策略，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，我们将使用来自相应TCGA数据集的miRNA/mRNA共表达谱和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共调节的网络模块。我们将研究四种类型癌症中的共同调控模块和每种特定癌症的独特模块。在目标3中，我们将使用已经可用的组织和匹配的正常样品以及建立的细胞系，实验验证目标2中常见调控模块中的选定miRNA及其靶标。该应用将是对前四种TCGA癌症中所有可用miRNA研究的首次系统研究。Aim 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; Aim 2的成功完成将为我们提供在这些癌症中在调控网络水平上对miRNA和TF共调控的全面探索;目标3的成功完成将验证我们的Meta方法和网络方法，帮助我们理解miRNA的调控机制，并为我们提供这些癌症的潜在治疗靶点。虽然是探索性的，但由于文献和TCGA中的大量数据，我们预计该项目是高度可行和及时的。这种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，这将可能导致有效预防，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.