Abstract
The strength and duration of NF-κB signaling are tightly controlled by multiple negative feedback mechanisms. However, in cancer cells, these feedback loops are overridden through unclear mechanisms to sustain oncogenic activation of NF-κB signaling. Previously, we demonstrated that overexpression of miR-30e* directly represses IκBα expression and leads to hyperactivation of NF-κB. Here, we report that miR-182 was overexpressed in a different set of gliomas with relatively lower miR-30e* expression and that miR-182 directly suppressed cylindromatosis (CYLD), an NF-κB negative regulator. This suppression of CYLD promoted ubiquitin conjugation of NF-κB signaling pathway components and induction of an aggressive phenotype of glioma cells both in vitro and in vivo. Furthermore, we found that TGF-β induced miR-182 expression, leading to prolonged NF-κB activation. Importantly, the results of these experiments were consistent with an identified significant correlation between miR-182 levels with TGF-β hyperactivation and activated NF-κB in a cohort of human glioma specimens. These findings uncover a plausible mechanism for sustained NF-κB activation in malignant gliomas and may suggest a new target for clinical intervention in human cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Cell Line, Tumor / transplantation
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Deubiquitinating Enzyme CYLD
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Genes, Reporter
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Glioma / genetics
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Glioma / metabolism*
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Glioma / pathology
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Humans
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I-kappa B Kinase / metabolism
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I-kappa B Proteins / deficiency
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Mice
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Mice, Nude
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MicroRNAs / antagonists & inhibitors
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MicroRNAs / biosynthesis
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MicroRNAs / genetics
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MicroRNAs / physiology*
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Neoplasm Invasiveness
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neovascularization, Pathologic / physiopathology
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Phosphorylation
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Protein Processing, Post-Translational
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RNA / biosynthesis
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RNA / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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RNA, Neoplasm / physiology*
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Signal Transduction / drug effects
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Smad Proteins / biosynthesis
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Smad Proteins / genetics
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Transcription, Genetic
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta / physiology*
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology
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Ubiquitination / drug effects
Substances
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I-kappa B Proteins
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MicroRNAs
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Mirn182 microRNA, human
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NF-kappa B
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NFKBIA protein, human
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Neoplasm Proteins
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Nfkbia protein, mouse
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RNA, Neoplasm
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RNA, recombinant
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Smad Proteins
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Transforming Growth Factor beta
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Tumor Suppressor Proteins
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NF-KappaB Inhibitor alpha
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RNA
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I-kappa B Kinase
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CYLD protein, human
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Deubiquitinating Enzyme CYLD