title: TGF-β induces miR-182 to sustain NF-κB activation in glioma subsets.
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* directly 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.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Zhongshan School of Medicine, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Song
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wu
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ying
authors.forename: Chuyong
authors.initials: C
authors.lastname: Lin
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D000074749:Deubiquitinating Enzyme CYLD; D017930:Genes, Reporter; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000172:deficiency; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D020672:I-kappa B Proteins; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; C000606205:Nfkbia protein, mouse; D012334:RNA, Neoplasm; C039919:RNA, recombinant; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D012313:RNA; D051550:I-kappa B Kinase; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD