Identification of a Core miRNA-Pathway Regulatory Network in Glioma by Therapeutically Targeting miR- 181d, miR-21, miR-23b, b-Catenin, CBP, and STAT3

The application of microRNAs (miRNAs) in the therapeutics of glioma and other human diseases is an area of intense interest. However, it’s still a great challenge to interpret the functional consequences of using miRNAs in glioma therapy. Here, we examined paired deep sequencing expression profiles of miRNAs and mRNAs from human glioma cell lines after manipulating the levels of miRNAs miR-181d,-21, and-23b, as well as transcriptional regulators b-catenin, CBP, and STAT3. An integrated approach was used to identify functional miRNA-pathway regulatory networks (MPRNs) responding to each manipulation. MiRNAs were identified to regulate glioma related biological pathways collaboratively after manipulating the level of either post-transcriptional or transcriptional regulators, and functional synergy and crosstalk was observed between different MPRNs. MPRNs responsive to multiple interventions were found to occupy central positions in the comprehensive MPRN (cMPRN) generated by integrating all the six MPRNs. Finally, we identified a core module comprising 14 miRNAs and five pathways that could predict the survival of glioma patients and represent potential targets for glioma therapy. Our results provided novel insight into miRNA regulatory mechanisms implicated in therapeutic interventions and could offe