Gene expression and network-based analysis reveals a novel role for hsa-miR-9 and drug control over the p38 network in glioblastoma multiforme progression.

ABSTRACT

BACKGROUND: Glioblastoma multiforme (GBM) is the most common, aggressive and malignant primary tumor of the brain and is associated with one of the worst 5-year survival rates among all human cancers. Identification of molecular interactions that associate with disease progression may be key in finding novel treatments. METHODS: Using five independent molecular and clinical datasets with a set of computational algorithms we were able to identify a gene-gene and gene-microRNA network that significantly stratifies patient prognosis. By combining gene expression microarray data with microRNA expression levels, copy number alterations, drug response and clinical data, combined with network knowledge, we were able to identify a single pathway at the core of glioblastoma. RESULTS: This network, the p38 network, and an associated microRNA, hsa-miR-9, facilitate prognostic stratification. The microRNA hsa-miR-9 correlated with network behavior and presents binding affinities with network members in a manner that suggests control over network behavior. A similar control over network behavior is possible through a set of drugs. These drugs are part of the treatment regimen for a subpopulation of the patients that participated in the TCGA study and for which the study provides clinical information. Interestingly, the patients that were treated with these specific sets of drugs, all of which targeted against p38 network members, demonstrate highly significant stratification of prognosis. CONCLUSIONS: Combined, these results call for attention to p38 network targeted treatment and present the p38 network-hsa-miR-9 control mechanism as critical in GBM progression.