title: MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma.
abstract: Highly malignant glioblastoma (GBM) is characterized by high genetic heterogeneity and infiltrative brain invasion patterns, and aberrant miRNA expression has been associated with hallmark malignant properties of GBM. The lack of effective GBM treatment options prompted us to investigate whether miRNAs would constitute promising therapeutic targets toward the generation of a gene therapy approach with clinical significance for this disease. Here, we show that microRNA-21 (miR-21) is upregulated and microRNA-128 (miR-128) is downregulated in mouse and human GBM samples, a finding that is corroborated by analysis of a large set of human GBM data from The Cancer Genome Atlas. Moreover, we demonstrate that oligonucleotide-mediated miR-21 silencing in U87 human GBM cells resulted in increased levels of the tumor suppressors PTEN and PDCD4, caspase 3/7 activation and decreased tumor cell proliferation. Cell exposure to pifithrin, an inhibitor of p53 transcriptional activity, reduced the caspase activity associated with decreased miR-21 expression. Finally, we demonstrate for the first time that miR-21 silencing enhances the antitumoral effect of the tyrosine kinase inhibitor sunitinib, whereas no therapeutic benefit is observed when coupling miR-21 silencing with the first-line drug temozolomide. Overall, our results provide evidence that miR-21 is uniformly overexpressed in GBM and constitutes a highly promising target for multimodal therapeutic approaches toward GBM.
authors.affiliation: CNC – Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Costa
authors.forename: Ana L
authors.initials: AL
authors.lastname: Cardoso
authors.forename: Clévio
authors.initials: C
authors.lastname: Nóbrega
authors.forename: Luís F
authors.initials: LF
authors.lastname: Pereira de Almeida
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.forename: Maria C
authors.initials: MC
authors.lastname: Pedroso de Lima
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage*; D016601:RNA-Binding Proteins / Q000235:genetics; D015398:Signal Transduction; D000077210:Sunitinib; D015854:Up-Regulation
chemical_list: D020533:Angiogenesis Inhibitors; D051017:Apoptosis Regulatory Proteins; D007211:Indoles; C545189:MIRN128 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D011758:Pyrroles; D016601:RNA-Binding Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077210:Sunitinib