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Micro RNA ‐302b‐inhibited E2F3 transcription factor is related to all trans retinoic acid‐induced glioma cell apoptosis
Author(s) -
Chen PengHsu,
Shih ChwenMing,
Chang WeiChiao,
Cheng ChiaHsiung,
Lin ChengWei,
Ho Kuohao,
Su PoChia,
Chen KuChung
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12820
Subject(s) - retinoic acid , gene knockdown , biology , apoptosis , microbiology and biotechnology , cancer research , glioma , viability assay , cell growth , chemistry , biochemistry , gene
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. Micro RNA s (mi RNA s) are small non‐coding RNA s that control gene expression. Several mi RNA s were identified to participate in ATRA ‐mediated cell differentiation. However, no studies have demonstrated whether mi RNA can enhance ATRA cytotoxicity, thereby resulting in cell apoptosis. This study investigated the effects of ATRA ‐mediated mi RNA 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.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.