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TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets.
- Source :
-
Journal of Clinical Investigation . Oct2012, Vol. 122 Issue 10, p3563-3578. 16p. - Publication Year :
- 2012
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 122
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 104383492
- Full Text :
- https://doi.org/10.1172/JCI62339