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

109 Citations (Scopus)

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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Glioma
Ubiquitin
Neoplasms
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Song, L., Liu, L., Wu, Z., Li, Y., Ying, Z., Lin, C., ... 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
Song, Libing ; Liu, Liping ; Wu, Zhiqiang ; Li, Yun ; Ying, Zhe ; Lin, Chuyong ; Wu, Jueheng ; Hu, Bo ; Cheng, Shi-Yuan ; Li, Mengfeng ; Li, Jun. / TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 10. pp. 3563-3578.
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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.",
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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, vol. 122, no. 10, pp. 3563-3578. https://doi.org/10.1172/JCI62339

TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets. / Song, Libing; Liu, Liping; Wu, Zhiqiang; Li, Yun; Ying, Zhe; Lin, Chuyong; Wu, Jueheng; Hu, Bo; Cheng, Shi-Yuan; Li, Mengfeng; Li, Jun.

In: Journal of Clinical Investigation, Vol. 122, No. 10, 01.10.2012, p. 3563-3578.

Research output: Contribution to journalArticle

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AU - Song, Libing

AU - Liu, Liping

AU - Wu, Zhiqiang

AU - Li, Yun

AU - Ying, Zhe

AU - Lin, Chuyong

AU - Wu, Jueheng

AU - Hu, Bo

AU - Cheng, Shi-Yuan

AU - Li, Mengfeng

AU - Li, Jun

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N2 - 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.

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