MicroRNA-302b-inhibited E2F3 transcription factor is related to all trans retinoic acid-induced glioma cell apoptosis

Authors

  • Peng-Hsu Chen,

    1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
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  • Chwen-Ming Shih,

    1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
    2. Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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  • Wei-Chiao Chang,

    1. Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
    2. Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
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  • Chia-Hsiung Cheng,

    1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
    2. Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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  • Cheng-Wei Lin,

    1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
    2. Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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  • Kuo-hao Ho,

    1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
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  • Po-Chia Su,

    1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
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  • Ku-Chung Chen

    Corresponding author
    1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
    2. Department of Biochemistry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
    • Address correspondence and reprint requests to Dr Ku-Chung Chen, Department of Biochemistry, Taipei Medical University, 250 Wu-Hsing Street, Xinyi District, Taipei 11031, Taiwan. E-mail: kuchung@tmu.edu.tw

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Abstract

All-trans retinoic acid (ATRA), a derivative of retinoid, is involved in the onset of differentiation and apoptosis in a wide variety of normal and cancer cells. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression. Several miRNAs were identified to participate in ATRA-mediated cell differentiation. However, no studies have demonstrated whether miRNA can enhance ATRA cytotoxicity, thereby resulting in cell apoptosis. This study investigated the effects of ATRA-mediated miRNA expression in activating apoptotic pathways in glioblastoma. First, we found that high-dose ATRA treatment significantly reduced cell viability, caspase-dependent apoptosis, endoplasmic reticular (ER) stress activation, and intracellular reactive oxygen species accumulation. From microarray data, miR-302b was analyzed as a putative downstream regulator upon ATRA treatment. Furthermore, we found that ATRA up-regulated miR-302b expression in a dose- and time-dependent manner through retinoic acid receptor α-mediated pathway. Overexpression and knockdown of miR-302b significantly influenced ATRA-mediated cytotoxicity. E2F3, an important transcriptional regulator of glioma proliferation, was validated to be a direct target gene of miR-302b. The miR-302b-reduced E2F3 levels were also identified to be associated with ATRA-mediated glioma cell death. These results emphasize that an ATRA-mediated miR-302b network may provide novel therapeutic strategies for glioblastoma therapy.

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We propose that high-dose all-trans retinoic acid (ATRA) treatment, a derivative of retinoid, significantly induces glioblastoma cell apoptosis via caspase-dependent apoptosis, endoplasmic reticular (ER) stress, and intracellular reactive oxygen species (ROS) accumulation. The miR-302b overexpression enhanced by ATRA-mediated retinoic acid receptor (RAR)α pathway was also identified. The E2F3 repression, a novel target gene of miR-302b, was involved in ATRA-induced glioblastoma cell cytotoxicity.

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