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Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases

Oncogene volume 31, pages 1884–1895 (2012)Cite this article

Abstract

MicroRNAs (miRNAs) carry out post-transcriptional control of a multitude of cellular processes. Aberrant expression of miRNA can lead to diseases, including cancer. Gliomas are aggressive brain tumors that are thought to arise from transformed glioma-initiating neural stem cells (giNSCs). With the use of giNSCs and human glioblastoma cells, we investigated the function of miRNAs in gliomas. We identified pro-neuronal miR-128 as a candidate glioma tumor suppressor miRNA. Decreased expression of miR-128 correlates with aggressive human glioma subtypes. With a combination of molecular, cellular and in vivo approaches, we characterize miR-128's tumor suppressive role. miR-128 represses giNSC growth by enhancing neuronal differentiation. miR-128 represses growth and mediates differentiation by targeting oncogenic receptor tyrosine kinases (RTKs) epithelial growth factor receptor and platelet-derived growth factor receptor-α. Using an autochthonous glioma mouse model, we demonstrated that miR-128 repressed gliomagenesis. We identified miR-128 as a glioma tumor suppressor that targets RTK signaling to repress giNSC self-renewal and enhance differentiation.

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Acknowledgements

We thank Israel Hernandez, Diego Piedrahita and Yngo Garcia for providing assistance with animal experiments, and Na Xu, Min Jeong Kye and Cecilia Conaco for scientific conversations and suggestions. Judith Czerny assisted in constructing target 3′-UTR constructs. Support for the project was from the WM Keck Foundation (KSK), the Miriam and Sheldon Adelson Medical Foundation (KSK), the National Science Foundation under grant No. PHY05-51164 (PN), the Myelin Repair Foundation (JCD and BAB), and the National Multiple Sclerosis Society (JCD and BAB). HZ work is supported by NIH grants (R55-CA136495, R01-CA136495). HZ is a Pew Scholar in Biomedical Sciences, supported by The Pew Charitable Trusts. DHR is an HHMI investigator.

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Authors and Affiliations

  1. Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, USA

    T Papagiannakopoulos, P Neveu, R M Gill & K S Kosik

  2. Department of Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, CA, USA

    T Papagiannakopoulos, R M Gill & K S Kosik

  3. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA

    D Friedmann-Morvinski & I M Verma

  4. Kavli Institute for Theoretical Physics, University of California at Santa Barbara, Santa Barbara, CA, USA

    P Neveu

  5. Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA

    J C Dugas & B A Barres

  6. Department of Pediatrics, University of California, San Francisco, CA, USA

    E Huillard & D H Rowitch

  7. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA

    E Huillard & D H Rowitch

  8. Institute of Molecular Biology, University of Oregon, Eugene, OR, USA

    C Liu & H Zong

  9. Howard Hughes Medical Institute, University of California, San Francisco, CA, USA

    D H Rowitch

  10. Department of Neurological Surgery, University of California, San Francisco, CA, USA

    D H Rowitch

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  1. T Papagiannakopoulos
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Correspondence to K S Kosik.

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Competing interests

K.S.K. owns stock in and serves on the board of Minerva Biotechnologies corporation and is on the scientific advisory board of Nocira Pharmaceuticals.

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Supplementary Information accompanies the paper on the Oncogene website

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Papagiannakopoulos, T., Friedmann-Morvinski, D., Neveu, P. et al. Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 31, 1884–1895 (2012). https://doi.org/10.1038/onc.2011.380

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