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MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

Cellular & Molecular Immunology volume 13, pages 658–668 (2016)Cite this article

Abstract

Although temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma, it is often non-curative due to drug resistance. To overcome the resistance of glioblastoma cells to TMZ, it is imperative to identify prognostic markers for outcome prediction and to develop chemo-sensitizing agents. Here, the gene expression profiles of TMZ-resistant and TMZ-sensitive samples were compared by microarray analysis, and mitogen-activated protein kinase kinase 2 (MEK2) was upregulated specifically in resistant glioma cells but not in sensitive tumor cells or non-tumor tissues. Moreover, a comprehensive analysis of patient data revealed that the increased level of MEK2 expression correlated well with the advancement of glioma grade and worse prognosis in response to TMZ treatment. Furthermore, reducing the level of MEK2 in U251 glioma cell lines or xenografted glioma models through shRNA-mediated gene knockdown inhibited cell proliferation and enhanced the sensitivity of cells toward TMZ treatment. Further analysis of tumor samples from glioma patients by real-time PCR indicated that an increased MEK2 expression level was closely associated with the activation of many drug resistance genes. Finally, these resistance genes were downregulated after MEK2 was silenced in vitro, suggesting that the mechanism of MEK2-induced chemo-resistance could be mediated by the transcriptional activation of these resistance genes. Collectively, our data indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ.

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Acknowledgements

This work was supported by NSFC81302187 and CWS14C063.

Author information

Author notes

  1. Hua He, Maojin Yao, Wenhao Zhang and Bangbao Tao: Hua He, Maojin Yao, Wenhao Zhang, and Bangbao Tao contributed equally to this work.

  2. Dr. Yi-Cheng Lu, Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China E-mail: yicheng_lu@sina.com

  3. Dr Hui Zong, Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia, USA E-mail: hz9s@eservices.virginia.edu

Authors and Affiliations

  1. Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, P.R.China

    Hua He, Yan Dong, Chenran Zhang, Yicheng Meng, Yuxin Li, Guohan Hu, Chun Luo & Yicheng Lu

  2. Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia, USA

    Maojin Yao & Hui Zong

  3. Department of Hematology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Wenhao Zhang

  4. Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Bangbao Tao & Feili Liu

  5. Department of Pathophysiology, Wannan Medical College, 22 Wenchang Road, Wuhu, 241002, China

    Shu Li

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He, H., Yao, M., Zhang, W. et al. MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment. Cell Mol Immunol 13, 658–668 (2016). https://doi.org/10.1038/cmi.2015.46

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