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Updated: May 18, 2026
Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets
Libing Song1, Liping Liu, Zhiqiang Wu
1State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Zhongshan School of Medicine, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
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.
Insights
MicroRNA-182 (miR-182) drives aggressive glioma by suppressing CYLD, a negative regulator of NF-κB signaling. Transforming growth factor-beta (TGF-β) induces miR-182, prolonging NF-κB activation in human gliomas.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Nuclear factor kappa B (NF-κB) signaling is crucial in cancer but its sustained activation in gliomas is not fully understood.
- Negative feedback mechanisms normally control NF-κB, but these are often disrupted in cancer cells.
Purpose of the Study:
- To investigate the role of microRNA-182 (miR-182) in the sustained activation of NF-κB signaling in gliomas.
- To elucidate the molecular mechanisms by which miR-182 contributes to glioma aggressiveness.
Main Methods:
- Analysis of miR-182 and miR-30e* expression in glioma samples.
- Luciferase reporter assays to confirm direct targeting of cylindromatosis (CYLD) by miR-182.
- In vitro and in vivo experiments to assess the impact of miR-182 on glioma cell phenotype.
- Investigation of the role of transforming growth factor-beta (TGF-β) in regulating miR-182 expression.
Main Results:
- miR-182 was overexpressed in gliomas with lower miR-30e* expression.
- miR-182 directly suppressed CYLD, a negative regulator of NF-κB.
- Suppression of CYLD by miR-182 promoted NF-κB pathway activation and aggressive glioma phenotypes.
- TGF-β induced miR-182 expression, leading to prolonged NF-κB activation.
- A positive correlation was observed between miR-182, TGF-β, and activated NF-κB in human gliomas.
Conclusions:
- miR-182 contributes to sustained NF-κB activation and aggressive glioma phenotypes by suppressing CYLD.
- The TGF-β/miR-182 axis represents a key mechanism for prolonged NF-κB activation in malignant gliomas.
- Targeting the miR-182 pathway may offer a novel therapeutic strategy for human gliomas.
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