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miR-1268a regulates ABCC1 expression to mediate temozolomide resistance in glioblastoma

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Abstract

Introduction

Temozolomide (TMZ) is the preferred chemotherapeutic drug approved for the Glioblastoma multiforme (GBM) treatment. However, resistance to TMZ is the most intractable challenge for treatment of GBM. Screening of miRNAs is becoming a novel strategy to reveal underlying mechanism of drug-resistance of human tumors.

Materials and methods

We conducted RNA sequencing (RNA-seq) for GBM cells treated continuously with TMZ 1 or 2 week or not. Bioinformatic analysis was used to predict targets of these altered miRNAs. Subsequently, we studied the potential role of miR-1268a in TMZ-resistance of GBM cells.

Results

Expression levels of 55 miRNAs were identified altering both after 1 and 2 weeks TMZ treatment. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to illuminate the biological implication and related pathways of predicted target genes. We showed that miR-1268a was downregulated after TMZ treatment and targeted ABCC1/MRP1, a membrane transporter contributing to drug resistance, using dual-luciferase assay. Furthermore, we confirmed overexpression of miR-1268a inhibited protein translation of ABCC1 and restored upregulated expression of ABCC1 due to TMZ. Inversely, knockdown of miR-1268a increased ABCC1 at protein level and enhanced upregulation of ABCC1 with TMZ treatment. In addition, our data indicated that miR-1268a enhanced TMZ sensitivity in GBM cells.

Conclusion

Through RNA-seq analysis, we discovered miR-1268a and elucidated its role in modulating TMZ-resistance of GBM cells by targeting ABCC1.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81372692, 81472315), National Key Technology Research and Development Program of the Ministry of Science and Technology of China (2014BAI04B01), Science and Technology Program of Guangdong (2016A020213006), Natural Science Foundation of Guangdong Province (2014A030313167).

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Author notes

  1. Yaomin Li, Yawei Liu and Jing Ren have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838#, Guangzhou, 510515, Guangdong, China

    Yaomin Li, Yawei Liu, Shengze Deng, Guozhong Yi, Yuping Peng & Songtao Qi

  2. Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China

    Yaomin Li, Shengze Deng, Guozhong Yi, Manlan Guo, Yuping Peng & Songtao Qi

  3. Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou, 510515, Guangdong, China

    Yawei Liu & Liang Zhao

  4. Southern Medical University, Guangzhou, 510515, Guangdong, China

    Jing Ren & Songren Shu

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  1. Yaomin Li
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Correspondence to Yuping Peng or Songtao Qi.

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This study has been approved by the Ethics Committee of Southern Medical University and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Li, Y., Liu, Y., Ren, J. et al. miR-1268a regulates ABCC1 expression to mediate temozolomide resistance in glioblastoma. J Neurooncol 138, 499–508 (2018). https://doi.org/10.1007/s11060-018-2835-3

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