Integrative genome analysis reveals an oncomir/ oncogene cluster regulating glioblastoma

Using a multidimensional genomic data set on glioblastoma fromThe Cancer Genome Atlas, we identified hsa-miR-26a as a cooper-ating component of a frequently occurring amplicon that alsocontains CDK4 and CENTG1, two oncogenes that regulate the RB1and PI3 kinase/AKT pathways, respectively. By integrating DNAcopy number, mRNA, microRNA, and DNA methylation data, weidentified functionally relevant targets of miR-26a in glioblastoma,including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate thatmiR-26a alone can transform cells and it promotes glioblastomacell growth in vitro and in the mouse brain by decreasing PTEN,RB1, and MAP3K2/MEKK2 protein expression, thereby increasingAKT activation, promoting proliferation, and decreasing c-JUN N-terminal kinase-dependent apoptosis. Overexpression of miR-26ain PTEN-competent and PTEN-deficient glioblastoma cells pro-moted tumor growth in vivo, and it further increased growth incells overexpressing CDK4 or CENTG1. Importantly, glioblastomapatients harboring this amplification displayed markedlydecreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 com-prise a functionally integrated oncomir/oncogene DNA cluster thatpromotes aggressiveness in human cancers by cooperatively tar-geting the RB1, PI3K/AKT, and JNK pathways.