title: MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-κB/IκBα negative feedback loop.
abstract: Constitutive activation of NF-κB is a frequent event in human cancers, playing important roles in cancer development and progression. In nontransformed cells, NF-κB activation is tightly controlled by IκBs. IκBs bind NF-κB in the cytoplasm, preventing it from translocating to the nucleus to modulate gene expression. Stimuli that activate NF-κB signaling trigger IκB degradation, enabling nuclear translocation of NF-κB. Among the genes regulated by NF-κB are those encoding the IκBs, providing a negative feedback loop that limits NF-κB activity. How transformed cells override this NF-κB/IκB negative feedback loop remains unclear. Here, we report in human glioma cell lines that microRNA-30e* (miR-30e*) directly targets the IκBα 3ι-UTR and suppresses IκBα expression. Overexpression of miR-30e* in human glioma cell lines led to hyperactivation of NF-κB and enhanced expression of NF-κB-regulated genes, which promoted glioma cell invasiveness in in vitro assays and in an orthotopic xenotransplantation model. These effects of miR-30e* were shown to be clinically relevant, as miR-30e* was found to be upregulated in primary human glioma cells and correlated with malignant progression and poor survival. Hence, miR-30e* provides an epigenetic mechanism that disrupts the NF-κB/IκBα loop and may represent a new therapeutic target and prognostic marker.
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Jiang
authors.forename: Chuyong
authors.initials: C
authors.lastname: Lin
authors.forename: Libing
authors.initials: L
authors.lastname: Song
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Baixue
authors.initials: B
authors.lastname: Chen
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ying
authors.forename: Lishan
authors.initials: L
authors.lastname: Fang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yan
authors.forename: Mian
authors.initials: M
authors.lastname: He
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D044127:Epigenesis, Genetic; D025461:Feedback, Physiological; D005910:Glioma / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D017077:Culture Media, Conditioned; D020672:I-kappa B Proteins; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha