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miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1

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Tumor Biology

Abstract

Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly with a high frequency. Glioblastoma stem cells (GSCs) causing resistance to drug therapy were considered to be one of key factors. The mechanisms underlying GSCs resistance to TMZ are not fully understood. MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance. Previous study showed that miR-125b was necessary for GSCs fission and for making stem cells insensitive to chemotherapy. Thus, exploring the functions and mechanisms of miR-125b action on TMZ-treated GSCs would be valuable. In this study, we found that miR-125b was up-regulated in TMZ-resistant cells, inhibition of which caused a marked increase of TMZ-induced cytotoxicity and apoptosis and a subsequent decrease in the resistance to TMZ in GSCs. Moreover, we demonstrated that the pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) was a direct target of miR-125b. Down-regulation of Bak1 inhibited TMZ-induced apoptosis and led to an increased resistance to TMZ. Restoring Bak1 expression recovered TMZ sensitivity on GSCs. Taken together; our data strongly support an important role for miR-125b on conferring TMZ resistance through targeting Bak1 expression.

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Acknowledgements

This work was supported by the China Natural Science Foundation (81000963, 81370062 and 81201976), Jiangsu Province's 333 Talent Program (BRA2011046), Six talents peak project in Jiangsu Province (WSN146), Jiangsu Province's Natural Science Foundation (BK2012670), Medical Research Foundation by Jiangsu Province Health Department (YG201301, Z201215 and Z201318), the Clinical Technology Development of Jiangsu University (JLY20120053), the Kunshan Social Development Foundation (KS1006, KS1009), and the Suzhou Social Development Foundation (SYS201063). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

All authors have declared the sources of research funding for this manuscript and have no financial or other contractual agreements that might cause (or be perceived as causes of) conflicts of interest.

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Authors and Affiliations

  1. Department of general surgery, The First People’s Hospital of Kunshan affiliated with Jiangsu University, Suzhou, 215300, People’s Republic of China

    Jian Chen

  2. Jiangsu University health science center, 3 Yizheng Road, Zhenjiang, 212001, People’s Republic of China

    Xingli Fu

  3. Department of Neurosurgery, Suzhou Kowloon Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Suzhou, 215021, People’s Republic of China

    Yi Wan, Zhimin Wang & Dongyi Jiang

  4. Department of Neurosurgery, The First People’s Hospital of Kunshan affiliated with Jiangsu University, Suzhou, 215300, People’s Republic of China

    Lei Shi

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  1. Jian Chen
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  3. Yi Wan
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  4. Zhimin Wang
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  5. Dongyi Jiang
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Correspondence to Xingli Fu or Lei Shi.

Additional information

Jian Chen, Xingli Fu, Yi Wan, Zhimin Wang and Dongyi Jiang contributed equally to this work.

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Chen, J., Fu, X., Wan, Y. et al. miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1. Tumor Biol. 35, 6293–6302 (2014). https://doi.org/10.1007/s13277-014-1821-4

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  • DOI: https://doi.org/10.1007/s13277-014-1821-4

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