MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA)-10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis.

The locus of microRNA-10b

“…38 The pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10, and NOTCH1. 39 This might also suggest that miR-10b could play a critical role in many types of human cancers.…”

Molecular prognostic factors in glioblastoma: state of the art and future challenges

“…Specifically, deregulation of these miRNAs has been detected in GBM, with a wide variety of functional roles in cell proliferation, apoptosis, cell cycle regulation, invasion, angiogenesis and glioma stem cell behavior [66]. Many reports have been published describing the ability of miRNAs to predict GBM patient survival [67][68][69][70][71][72][73][74][75][76][77]. For example, Ben-Hamo and Efroni studied five independent datasets and identified a gene-miRNA network comprising of p38 and its associated miRNA miR-9, which can stratify GBM patients into prognostic subgroups [67].…”

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

“…Augmented miR‐10b expression levels are correlated with higher grade gliomas, 72, 73 and indeed, GBM cells display reduced growth, invasion, and angiogenesis, as well as enhanced cell death when treated with antisense oligonucleotides to miR‐10b 73. Further, in an orthotopic human glioma mouse model, inhibition of miR‐10b diminished the growth, invasiveness, and angiogenicity of glioma cells in the brain, significantly prolonging the survival of glioma‐bearing mice 74.…”