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TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets
Libing Song, … , Mengfeng Li, Jun Li
Libing Song, … , Mengfeng Li, Jun Li
Published September 24, 2012
Citation Information: J Clin Invest. 2012;122(10):3563-3578. https://doi.org/10.1172/JCI62339.
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Research Article Article has an altmetric score of 7

TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets

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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.

Authors

Libing Song, Liping Liu, Zhiqiang Wu, Yun Li, Zhe Ying, Chuyong Lin, Jueheng Wu, Bo Hu, Shi-Yuan Cheng, Mengfeng Li, Jun Li

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Figure 7

Suppression of miR-182 inhibits NF-κB activity and malignant properties of PDGCs.

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Suppression of miR-182 inhibits NF-κB activity and malignant properties ...
(A) Real-time PCR analysis of miR-182 expression in NHAs and PDGCs derived from 2 separate glioma specimens. Transcript levels were normalized by U6 expression. (B) NF-κB reporter activities in PDGCs derived from 2 separate glioma specimens transfected with a negative control or a miR-182 inhibitor. (C) EMSA of endogenous NF-κB activity showed a marked decrease in PDGCs transfected with the miR-182 inhibitor. OCT-1 DNA-binding complexes were used as a control. (D) Luciferase activity of CYLD-3′UTR in PDGCs transfected with negative control or the miR-182 inhibitor. (E) WB of K63-linked poly-Ub of RIP1 and NEMO and K48-linked poly-Ub of IκBα in negative control– or miR-182 inhibitor–transfected PDGCs treated with 10 ng/ml TNF-α. (F) Representative images and quantification of negative control– or miR-182 inhibitor–transfected PDGCs analyzed in a clonogenic assay (see Supplemental Methods). (G) Representative images and quantification of invaded cells analyzed using a Transwell matrix penetration assay. Scale bars: 50 μm. (H) Representative images and quantification of HUVECs cultured on Matrigel-coated plates with conditioned medium from negative control– or miR-182 inhibitor–transfected PDGCs (see Supplemental Methods). Scale bars: 100 μm. Error bars represent mean ± SD from 3 independent experiments. *P < 0.05.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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