An Integrative Systems Analysis of High-grade Glioma Cell Lines: TLRs, Wnt, BRCA1, Netrins, STXBP1 and MDH1 Provide Putative Molecular Targets for Therapeutic Intervention

Gliomas are the most common form of brain tumor, originate from glial cells and characterized by rapidly proliferating cells frequently associated with an invasive phenotype. Several focused studies have successfully demonstrated the genetic origin of these tumors; however, a systems level study to provide comprehensive overview of complex molecular alterations associated with glioma pathogenesis is essential. In this study the main aim was to identify molecular targets associated with high-grade gliomas using systems based investigation, and to identify pathways, molecular networks and functional modules associated with curated genes/ proteins that have altered expression in highgrade glioma cell lines. DAVID and PANTHER analysis tools were used to identify molecular functions, and functional annotation clusters associated with curated dataset. IPA, MetaCore and GeneSpring were used to study the complex interaction of curated molecules and identification of associated signaling pathways. The signaling pathways mediated by TLRs, IL-8, STATs and Wnt, which regulate malignant behavior of high-grade gliomas, were identified as candidates for therapeutic targets. STXBP1, PDK1, MAP3K8 and HIF1A/ARNT appeared as most significant modules in GeneSpring functional analysis. GLIPR1 and MDH1 were identified as potential candidates for further study in gliomas. This study represents a systems level approach to extract biologically relevant information from existing resources and provide new contexts for future research in gliomas.