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  • MicroRNA Targetting MGMT Enhances Sensitivity to Themozolomimde Therapy in Glioblastoma

    Final Number:

    Daisuke Ogawa MD, PhD; Keisuke Miyake MD PhD; Takashi Tamiya MD; E. Antonio Chiocca MD, PhD; Jakub Godlewski PhD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2014 Annual Meeting

    Introduction: It is well known that O6-methylguanine-DNA methyltransferase (MGMT) is related to resistance of aggressive brain tumor glioblastoma (GBM) to DNA alkylating agent Temozolomide (TMZ) therapy. In this study, we searched for microRNA that regulate MGMT expression and give better sensitivity to TMZ.

    Methods: We picked up 6 microRNAs out of tens of candidates from several binding site prediction softwares, which have complementary seed region with 3'-UTR of MGMT messenger RNA (mRNA).

    Results: One out of 6 microRNAs down regulated MGMT mRNA and protein more than 40% in both T98G glioma cell line and primary GBM cell line (GBM30). Direct interaction between miR-655 and 3’-UTR of MGMT mRNA was confirmed by luciferase reporter assay. Sensitivity to TMZ was increased in microRNA transfected T98G cells as same level as U87MG which cell line is not expressing MGMT and the T98G cells down regulated MGMT by siRNA. We will also show that GBM30 expressing microRNA transplanted in nude mice survived better than control with injection of TMZ in vivo.

    Conclusions: Thus, this microRNA has endogenous mechanism that increase chemo-sensitivity to TMZ by suppressing drug resistance gene MGMT. Further study of microRNA effecting cell proliferation and survival related to TMZ will be discussed. This study will provide a new target to enhance efficacy of chemotherapy.

    Patient Care: This study will improve drug sensitivity in glioblastoma patients, thus, prolong their survival.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of how to manage drug resistance gene, 2) Discuss, in small groups,drug sensitivity, 3) Identify an effective treatment for glioblastoma.


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