title: Effect of miR-21 and miR-30b/c on TRAIL-induced apoptosis in glioma cells.
abstract: Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, survival of patients remains poor. To define novel pathways that regulate susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in glioma, we have performed genome-wide expression profiling of microRNAs (miRs). We show that in TRAIL-resistant glioma cells, levels of different miRs are increased, and in particular, miR-30b/c and -21. We demonstrate that these miRs impair TRAIL-dependent apoptosis by inhibiting the expression of key functional proteins. T98G-sensitive cells treated with miR-21 or -30b/c become resistant to TRAIL. Furthermore, we demonstrate that miR-30b/c and miR-21 target respectively the 3' untranslated region of caspase-3 and TAp63 mRNAs, and that those proteins mediate some of the effects of miR-30 and -21 on TRAIL resistance, even in human glioblastoma primary cells and in lung cancer cells. In conclusion, we show that high expression levels of miR-21 and -30b/c are needed to maintain the TRAIL-resistant phenotype, thus making these miRs as promising therapeutic targets for TRAIL resistance in glioma.
authors.affiliation: Department of Cellular and Molecular Biology and Pathology, 'Federico II' University of Naples, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Quintavalle
authors.forename: E
authors.initials: E
authors.lastname: Donnarumma
authors.forename: M
authors.initials: M
authors.lastname: Iaboni
authors.forename: G
authors.initials: G
authors.lastname: Roscigno
authors.forename: M
authors.initials: M
authors.lastname: Garofalo
authors.forename: G
authors.initials: G
authors.lastname: Romano
authors.forename: D
authors.initials: D
authors.lastname: Fiore
authors.forename: P
authors.initials: P
authors.lastname: De Marinis
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.forename: G
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C524940:MIRN21 microRNA, human; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D053148:Caspase 3