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

The strength and duration of NF-kappa B 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-kappa B signaling. Previously, we demonstrated that overexpression of miR-30e* directly represses I kappa B alpha expression and leads to hyperactivation of NF-kappa B. 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-kappa B negative regulator. This suppression of CYLD promoted ubiquitin conjugation of NF-kappa B signaling pathway components and induction of an aggressive phenotype of glioma cells both in vitro and in vivo. Furthermore, we found that TGF-beta induced miR-182 expression, leading to prolonged NF-kappa B activation. Importantly, the results of these experiments were consistent with an identified significant correlation between miR-182 levels with TGF-beta hyperactivation and activated NF-kappa B in a cohort of human glioma specimens. These findings uncover a plausible mechanism for sustained NF-kappa B activation in malignant gliomas and may suggest a new target for clinical intervention in human cancer.