Abstract

Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival of less than 15 months. Therefore, there is a critical need to develop novel therapeutic strategies for GBM. This study aimed to assess the prognostic value of miR-4516 and investigate its oncogenic functions and the underlying cellular and molecular mechanisms in GBM. To determine the correlation between miR-4516 expression and overall survival of patients with GBM, total RNAs were isolated from 268 FFPE tumor samples, miR expression was assayed (simultaneously) using the nCounter human miRNA v3a assay followed by univariable and multivariable survival analyses. Further, in vitro and in vivo studies were conducted to define the role of miR-4516 in GBM tumorigenesis and the underlying molecular mechanisms. Upon multivariable analysis, miR-4516 was correlated with poor prognosis in GBM patients (HR = 1.49, 95%CI: 1.12–1.99, P = 0.01). Interestingly, the significance of miR-4516 was retained including MGMT methylation status. Overexpression of miR-4516 significantly enhanced cell proliferation and invasion of GBM cells both in vitro and in vivo. While conducting downstream targeting studies, we found that the tumor-promoting function of miR-4516, in part, was mediated by direct targeting of PTPN14 (protein tyrosine phosphatase, non-receptor type 14) which, in turn, regulated the Hippo pathway in GBM. Taken together, our data suggest that miR-4516 represents an independent negative prognostic factor in GBM patients and acts as a novel oncogene in GBM, which regulates the PTPN14/Hippo pathway. Thus, this newly identified miR-4516 may serve as a new potential therapeutic target for GBM treatment.

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Acknowledgements

We thank the T&P Bohnenn Fund for Neuro-Oncology Research (grant to P.A.R.), the Ohio State University (OSU) Comprehensive Cancer Center Small Animal Imaging Core, and the Ohio State University (OSU) Comprehensive Cancer Center Pathology Core Facility supported in part by grant P30 CA016058, National Cancer Institute, Bethesda, MD.

Funding

This work was supported by National Cancer Institute [R01CA169368 (to A.C.), R01CA11522358 (to A.C.), R01CA1145128 (to A.C.), R01CA108633 (to A.C.), R01CA188228 (to A.C., R.B., K.L., and J.B.), 1RC2CA148190 (to A.C.), and U10CA180850–01 (to A.C.)]; A Brain Tumor Funders Collaborative Grant (to A.C.); Ohio State University Comprehensive Cancer Center Award (to A.C.).

Author information

Author notes

  1. These authors contributed equally: Tiantian Cui, Erica H. Bell

Affiliations

  1. Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, OH, 43210, USA

    • Tiantian Cui
    • , Erica H. Bell
    • , Aline Paixao Becker
    • , Pooja Manchanda Gulati
    • , Linlin Yang
    • , Ziyan Liu
    • , Jessica L. Fleming
    • , S. Jaharul Haque
    •  & Arnab Chakravarti
  2. Department of Biomedical Informatics, The Ohio State University Center for Biostatistics, Columbus, OH, USA

    • Joseph McElroy
  3. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

    • Marjolein Geurts
    •  & Pierre Robe
  4. Department of Internal Medicine, Division of Nephrology, Columbia University, New York, NY, 10032, USA

    • Nikol Mladkova
  5. The Ohio State University, Columbus, OH, 43210, USA

    • Ashley Gray
  6. The Ohio State University College of Medicine, Columbus, OH, 43210, USA

    • Kevin Liu
  7. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    • Jill S. Barnholtz-Sloan
  8. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    • Keith L. Ligon
  9. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    • Keith L. Ligon
    •  & Rameen Beroukhim
  10. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    • Rameen Beroukhim

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The authors declare that they have no conflict of interest.

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Correspondence to Arnab Chakravarti.

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DOI

https://doi.org/10.1038/s41388-018-0601-9