Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship

Abstract

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 Nterminal 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.

MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation

“…Our current study expands these previous findings and shows that, in addition to embryonic stem cell differentiation, TETs, together with miR-26a, may also play a role in later-stage cell differentiation, such as the endocrine pancreas. Beside TETs and TDG, other known miR-26a targets, including EZH2, PTEN, and pRB (40,44), may also contribute to the function of miR-26a in cell differentiation.…”

The miR-17-92 MicroRNA Cluster Is Regulated by Multiple Mechanisms in B-Cell Malignancies

“…[1][2][3][4] Various miRNAs are overexpressed or underexpressed in different types of cancer in humans and may function as either tumor suppressors or oncogenes. [5][6][7][8][9][10][11][12][13] A cluster of six miRNAs (miR-17-92, comprising miR-17, miR18a, miR-20a, miR-19a, miR-19b-1, and miR-92a-1) is processed from the transcript of C13orf25 (also known as MIR17HG or MIRHG1), a gene amplified in some lymphomas and solid tumors 5,14 -17 and overexpressed in a large fraction of lymphomas. 5 Overexpression of miR-17-92 accelerates lymphomagenesis in mouse models.…”

miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics

“…[30][31][32] miR26a promotes transformation by targeting PTEN and retinoblastoma 1 (RB1), 2 of the most frequently deleted tumor suppressors in GBM, and by modulating JNK activation. 33,34 Finally, by regulating Notch, RTK and Smad4 signaling, miR-34a was identified as a tumor suppressor in proneural tumors. [35][36][37] In particular, applying a Context Likelihood of Relatedness (CLR) algorithm, Chin and collegues sought to identify high-priority miRNA-mRNA relationships in the TCGA data set.…”