Effect of miR-21 and miR-30b/c on TRAIL-induced apoptosis in glioma cells

• Published in: Oncogene Vol. 32; no. 34; pp. 4001 - 4008
• Main Authors: Quintavalle, C, Donnarumma, E, Iaboni, M, Roscigno, G, Garofalo, M, Romano, G, Fiore, D, De Marinis, P, Croce, C M, Condorelli, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.08.2013; Nature Publishing Group
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; Apoptosis; Apoptosis - drug effects; Blotting, Northern; Blotting, Western; Brain cancer; Brain tumors; Care and treatment; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase-3; Cell Biology; Cell Line, Tumor; Cytokines; Drug Resistance, Neoplasm - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic aspects; Genomes; Glioblastoma; Glioblastoma multiforme; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma cells; Health aspects; HEK293 Cells; Human Genetics; Humans; Internal Medicine; Lung cancer; Medicine; Medicine & Public Health; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Oligonucleotide Array Sequence Analysis; Oncology; original-article; Phenotypes; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Therapeutic targets; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL protein; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Cells, Cultured; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; United States; treatment; microRNA; apoptosis; glioblastoma; TRAIL; therapy
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.410

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.