Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship.
Using a multidimensional genomic data set on glioblastoma from The Cancer Genome Atlas, we identified hsa-miR-26a as a cooperating component of a frequently occurring amplicon that also contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA copy number, mRNA, microRNA, and DNA methylation data, we identified functionally relevant targets of miR-26a in glioblastoma, including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that miR-26a alone can transform cells and it promotes glioblastoma cell growth in vitro and in the mouse brain by decreasing PTEN, RB1, and MAP3K2/MEKK2 protein expression, thereby increasing AKT activation, promoting proliferation, and decreasing c-JUN N-terminal kinase-dependent apoptosis. Overexpression of miR-26a in PTEN-competent and PTEN-deficient glioblastoma cells promoted tumor growth in vivo, and it further increased growth in cells overexpressing CDK4 or CENTG1. Importantly, glioblastoma patients harboring this amplification displayed markedly decreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways.
Kim
Hyunsoo
H
Department of Medicine, Harvard Partners Center for Genetics and Genomics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Huang
Wei
W
Jiang
Xiuli
X
Pennicooke
Brenton
B
Park
Peter J
PJ
Johnson
Mark D
MD
D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D030561:Databases, Nucleic Acid; D019204:GTP-Binding Proteins / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D018628:Gene Dosage; D023281:Genomics; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics; D005810:Multigene Family; D009368:Neoplasm Transplantation; D009857:Oncogenes; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D051358:Cyclin-Dependent Kinase 4; D017931:DNA Primers; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D016160:Retinoblastoma Protein; C528163:MIRN26 microRNA, human; C495900:CDK4 protein, human; C494929:PTEN protein, human; C485997:AGAP2 protein, human