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

Oncogene volume 34, pages 1619–1628 (2015)Cite this article

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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.

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Acknowledgements

We appreciate Xinna Zhang at the MicroRNA Core Facility for help with miRNA hybridization experiments, Zhimin Lu at the Department of Neuro-Oncology-Research for helpful comments, and Kathryn L Hale at the Department of Scientific Publications at MD Anderson Cancer Center for manuscript editing. This work was supported by grants from the National Institutes of Health (CA098503 to WZ and IS, CA141432 and CA143835 to WZ and CA115729 and CA127001 to FFL), IVY, Elias and Broach Foundations, the Gene Pennebaker Brain Cancer Fund, and the Academy of Finland (grant 259038 to KG); Xia Li was supported by a fellowship from The Fourth Military Medical University (4138C4IA1Z). Lynette Moore was supported by a fellowship from the American Cancer Society.

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Author notes

  1. X Li and Y Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Li, Y Liu, K J Granberg, L M Moore, P Ji, G N Fuller & W Zhang

  2. Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi’an, China

    X Li & Q Wang

  3. Department of Signal Processing, Tampere University of Technology, Tampere, Finland

    K J Granberg & M Nykter

  4. Department of Pathology, Fimlab Laboratories and University of Tampere, Tampere, Finland

    K J Granberg & H Haapasalo

  5. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Gumin & F F Lang

  6. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    E P Sulman

  7. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G A Calin

  8. Non-coding RNA Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G A Calin & W Zhang

  9. Institute of Biomedical Technology, University of Tampere, Tampere, Finland

    M Nykter

  10. Institute for Systems Biology, Seattle, WA, USA

    I Shmulevich

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Li, X., Liu, Y., Granberg, K. et al. Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma. Oncogene 34, 1619–1628 (2015). https://doi.org/10.1038/onc.2014.98

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