TGF-? induces miR-182 to sustain NF-?B activation in glioma subsets.

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

SUBMITTER: Song L 

PROVIDER: S-EPMC3589141 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature