Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers.

Author Summary

Several recent studies have implicated the critical role of microRNAs (miRNAs) in the pathogenesis of glioblastoma (GBM), the most common and lethal brain tumor in humans, suggesting that miRNAs may be clinically useful as biomarkers for brain tumors and other cancers. However, to date, the regulatory mechanisms of miRNAs in GBM are unclear. In this study, we have systematically constructed miRNA and transcription factor (TF) mediated regulatory networks specific to GBM. To demonstrate that the GBM-specific regulatory network contains functional modules that may composite of critical miRNA components, we extracted a subnetwork including GBM-related genes involved in the Notch signaling pathway. Through network topological and functional analyses of the Notch signaling pathway subnetwork, several critical miRNAs have been identified, some of which have been reinforced by previous studies. This study not only provides novel miRNAs for further experimental design but also develops a novel computational framework to construct a miRNA-TF combinatory regulatory network for a specific disease.