TGF-beta induces miR-182 to sustain NF-kappa B activation in glioma subsets

作者：Song Libing; Liu Liping; Wu Zhiqiang; Li Yun; Ying Zhe; Lin Chuyong; Wu Jueheng; Hu Bo; Cheng Shi Yuan; Li Mengfeng; Li Jun^*

来源：Journal of Clinical Investigation, 2012, 122(10): 3563-3578.

DOI：10.1172/JCI62339

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.

• 单位
  西北大学