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Oncogene. 2015 Mar 26;34(13):1619-1628. doi: 10.1038/onc.2014.98. Epub 2014 Apr 21.

Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma.

Author information

1
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, China.
3
Department of Signal Processing, Tampere University of Technology, Tampere, Finland.
4
Department of Pathology, Fimlab Laboratories and University of Tampere, Tampere, Finland.
5
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
6
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
7
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
8
Department of Non-coding RNA center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
9
Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
10
Institute for Systems Biology, Seattle, Washington, USA.
#
Contributed equally

Abstract

MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets EGFR, CDK6 and Bcl-xL, whereas miR-491-3p targets IGFBP2 and CDK6. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary Ink4a-Arf-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore, MIR-491 is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.

PMID:
24747968
PMCID:
PMC4205227
DOI:
10.1038/onc.2014.98
[Indexed for MEDLINE]
Free PMC Article

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