Abstract
Notch pathway plays critical role in stem cell maintenance and angiogenesis, as well as cell fate decisions of cancer. However, concrete mechanisms of notch pathway regulation in glioma were not well known, especially mediated by microRNAs. In this study, we identified a brain-specific miRNA, miR-524-5p, which was associated with the pathological grade and overall survival of gliomas. Restorated expression of miR-524-5p in glioma suppressed cell proliferation and invasion both in vitro and in vivo. Using bioinformatics and biological approaches, we found that Jagged-1 and Hes-1, two key components of notch pathway, were direct targets of miR-524-5p. Knocking down of Jagged-1 or Hes-1 partially phenocopied miR-524-5p re-expression, whereas forced expression of Jagged-1 or Hes-1 reversed the effects of miR-524-5p on proliferation and invasion of glioma. Moreover, miR-524-5p levels in glioma samples were inversely correlated with Jagged-1 and Hes-1 and their overexpressions were associated with poor survival. Thus, we have identified that miR-524-5p behaves as a tumor suppressor by negatively targeting Jagged-1 and Hes-1 and provides an additional option to inhibit this oncogene in gliomas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Brain Neoplasms / mortality
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Calcium-Binding Proteins / antagonists & inhibitors
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Cell Movement
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Cell Proliferation
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Chromatin Immunoprecipitation
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Female
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Gene Expression Profiling
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Genes, Tumor Suppressor*
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Glioma / genetics
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Glioma / metabolism*
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Glioma / mortality
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Homeodomain Proteins / antagonists & inhibitors
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Immunoenzyme Techniques
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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Luciferases / metabolism
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Nude
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MicroRNAs / genetics*
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Serrate-Jagged Proteins
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Transcription Factor HES-1
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers, Tumor
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Calcium-Binding Proteins
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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MIRN542 microRNA, human
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Membrane Proteins
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MicroRNAs
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RNA, Messenger
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RNA, Small Interfering
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Serrate-Jagged Proteins
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Transcription Factor HES-1
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HES1 protein, human
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Luciferases