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MicroRNA‐124 Negatively Regulates Nuclear Receptor Nur77
Author(s) -
Farmer Alexa,
Beard Jordan A,
Takwi Apana,
Wang Yueming,
Chen Taosheng
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.867.1
Subject(s) - nerve growth factor ib , biology , microrna , downregulation and upregulation , microbiology and biotechnology , cell growth , cancer research , three prime untranslated region , transcription factor , nuclear receptor , untranslated region , messenger rna , genetics , gene
The nuclear receptor Nur77 is commonly upregulated in adult cancers and has oncogenic functions. Nur77 is an immediate‐early response gene that acts as a transcription factor to promote proliferation and protect the cell from apoptosis. Conversely, Nur77 can translocate to the mitochondria and induce apoptosis upon treatment with various cytotoxic agents. Because Nur77 is upregulated in cancer and may have a role in cancer progression, it is of interest to understand the mechanism controlling its expression. MicroRNAs (miRNAs) are responsible for inhibiting translation of their target genes by binding to the 3′UTR and either degrading the mRNA or preventing it from being translated into protein, thereby making these non‐coding endogenous RNAs vital regulators of every cellular process. Several miRNAs have been predicted to target Nur77; however, strong evidence showing the regulation of Nur77 by any miRNA is lacking. In this study we used a luciferase reporter assay containing the 3′UTR of Nur77 to screen 296 miRNAs and found that miR‐124, the most abundant miRNA in the brain with a role in promoting neuronal differentiation, caused the greatest reduction in luciferase activity. Interestingly, we discovered an inverse relationship in Daoy medulloblastoma cells and undifferentiated granule neuron precursors (GNPs) where Nur77 is upregulated and miR‐124 is downregulated. Further elevating Nur77 levels in Daoy cells by exogenous expression increased proliferation and viability, but knocking down Nur77 via siRNA resulted in the opposite phenotype. Importantly, exogenous expression of miR‐124 reduced Nur77 expression, cell viability, proliferation, and tumor spheroid size in 3D culture. In all, we have discovered miR‐124 to be downregulated in instances of medulloblastoma in which Nur77 is upregulated, resulting in a proliferative state that abets cancer progression. This study provides evidence for increasing miR‐124 expression as a potential therapy for cancers with elevated levels of Nur77. Support or Funding Information This work was supported by the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children's Research Hospital, and the National Institutes of Health [Grants RO1GM086415, RO1GM110034, & P30‐CA21765].