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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

115 Scopus citations

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*irectly 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.

Original languageEnglish (US)
Pages (from-to)3563-3578
Number of pages16
JournalJournal of Clinical Investigation
Volume122
Issue number10
DOIs
StatePublished - Oct 1 2012

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Song, L., Liu, L., Wu, Z., Li, Y., Ying, Z., Lin, C., Wu, J., Hu, B., Cheng, S. Y., Li, M., & Li, J. (2012). TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets. Journal of Clinical Investigation, 122(10), 3563-3578. https://doi.org/10.1172/JCI62339