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miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme

Oncogene volume 32, pages 1155–1163 (2013)Cite this article

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Abstract

Chromosome 1p36.23 is frequently deleted in glioblastoma multiforme (GBM). miR-34a localizes in this region. Our experiments found that miR-34a was often deleted and epidermal growth factor receptor (EGFR) was frequently amplified in genomic DNA of 55 GBMs using single-nucleotide polymorphism DNA microarray. Notably, we found that the mean survival time was significantly shortened for patients whose GBMs had both EGFR amplification and miR-34a deletion. Expression of miR-34a was significantly lower in GBM samples compared with normal brain tissue. Forced expression of miR-34a in GBM cells decreased their ability to migrate and profoundly decreased their levels of cyclin-A1, -B1, -D1, and -D3, as well as cyclin-dependent kinase and increased expression of cyclin kinase inhibitor proteins (p21, p27). Also, human GBM cells (U251) stable overexpressing mir-34a formed smaller tumors when growing as xenografts in immunodeficient mice compared with wild-type U251 GBM cells. Furthermore, the protein expression of EGFR decreased in the cells with forced overexpression of miR-34a. Additional studies showed that mir-34a targeted Yin Yang-1 (YY1) and YY1 is a transcription factor that can stimulate the expression of EGFR. Thus, our data suggest that miR-34a acts as a tumor suppressor by inhibiting growth of GBM cells in vitro and in vivo associated with moderating the expression of cell-cycle proteins and EGFR. Moreover, we discovered for the first time that both deletion of miR-34a and amplification of EGFR were associated with significantly decreased overall survival of GBM patients.

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Acknowledgements

This work was supported in part by the National Institutes of Health grant 1U54CA143930-02 and 5R01CA026038-32, Tom Collier Foundation, A *STAR award of Singapore (HPK); a grant from the Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center (KLB); NSFC grant 81071788, ‘985 project’ of Sun Yat-sen University. HPK is a member of the Molecular Biology Institute and Jonsson Comprehensive Cancer Center at UCLA, and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine. This study is in loving memory of Matt Schreck.

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Author notes

  1. K L Black and H Phillip Koeffler: These authors contributed equally to this work and should be considered co-last authors.

Authors and Affiliations

  1. Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    D Yin

  2. Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA

    D Yin, N Kawamata, A Leiter, M Ham & H Phillip Koeffler

  3. Regeneration Medicine of Hematopoiesis, School of Medicine, University of Tokyo, Tokyo, Japan

    S Ogawa

  4. Los Angeles Biomedical Research Institute at the Harbor UCLA Medical Center, 1124 West Carson Street, Torrance, CA, USA

    D Li

  5. Department of Pathology, UCLA School of Medicine, Los Angeles, CA, USA

    N B Doan & J W Said

  6. Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA

    K L Black

  7. Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System,

    H Phillip Koeffler

  8. Cancer Science Institute, National University of Singapore, Singapore,

    H Phillip Koeffler

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  1. D Yin
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Correspondence to D Yin.

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Yin, D., Ogawa, S., Kawamata, N. et al. miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme. Oncogene 32, 1155–1163 (2013). https://doi.org/10.1038/onc.2012.132

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