Therapeutic potential of targeting micro RNA ‐10b in established intracranial glioblastoma: first steps toward the clinic
Open Access
- 10 February 2016
- journal article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 8 (3), 268-287
- https://doi.org/10.15252/emmm.201505495
Abstract
MicroRNA‐10b (miR‐10b) is a unique oncogenic miRNA that is highly expressed in all GBM subtypes, while absent in normal neuroglial cells of the brain. miR‐10b inhibition strongly impairs proliferation and survival of cultured glioma cells, including glioma‐initiating stem‐like cells (GSC). Although several miR‐10b targets have been identified previously, the common mechanism conferring the miR‐10b‐sustained viability of GSC is unknown. Here, we demonstrate that in heterogeneous GSC, miR‐10b regulates cell cycle and alternative splicing, often through the non‐canonical targeting via 5′UTRs of its target genes, including MBNL1‐3, SART3, and RSRC1. We have further assessed the inhibition of miR‐10b in intracranial human GSC‐derived xenograft and murine GL261 allograft models in athymic and immunocompetent mice. Three delivery routes for the miR‐10b antisense oligonucleotide inhibitors (ASO), direct intratumoral injections, continuous osmotic delivery, and systemic intravenous injections, have been explored. In all cases, the treatment with miR‐10b ASO led to targets’ derepression, and attenuated growth and progression of established intracranial GBM. No significant systemic toxicity was observed upon ASO administration by local or systemic routes. Our results indicate that miR‐10b is a promising candidate for the development of targeted therapies against all GBM subtypes.Keywords
Funding Information
- National Brain Tumor Society
This publication has 68 references indexed in Scilit:
- Co-inhibition of microRNA-10b and microRNA-21 exerts synergistic inhibition on the proliferation and invasion of human glioma cellsInternational Journal of Oncology, 2012
- An alternative mode of microRNA target recognitionNature Structural & Molecular Biology, 2012
- Targeted therapy for high-grade glioma with the TGF- 2 inhibitor trabedersen: results of a randomized and controlled phase IIb studyNeuro-Oncology, 2010
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neuronsGenes & Development, 2007
- Glioma stem cells promote radioresistance by preferential activation of the DNA damage responseNature, 2006
- Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human GliomasCancer Research, 2005
- Gene Expression Omnibus: NCBI gene expression and hybridization array data repositoryNucleic Acids Research, 2002
- Single bilayer liposomes prepared without sonicationBiochimica et Biophysica Acta (BBA) - Biomembranes, 1973