Nature communications, 2019-01, Vol.10 (1), p.442-442, Article 442
2019
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- Autor(en) / Beteiligte
- Titel
- The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma
- Ist Teil von
- Nature communications, 2019-01, Vol.10 (1), p.442-442, Article 442
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- MicroRNA deregulation is a consistent feature of glioblastoma, yet the biological effect of each single gene is generally modest, and therapeutically negligible. Here we describe a module of microRNAs, constituted by miR-124, miR-128 and miR-137, which are co-expressed during neuronal differentiation and simultaneously lost in gliomagenesis. Each one of these miRs targets several transcriptional regulators, including the oncogenic chromatin repressors EZH2, BMI1 and LSD1, which are functionally interdependent and involved in glioblastoma recurrence after therapeutic chemoradiation. Synchronizing the expression of these three microRNAs in a gene therapy approach displays significant anticancer synergism, abrogates this epigenetic-mediated, multi-protein tumor survival mechanism and results in a 5-fold increase in survival when combined with chemotherapy in murine glioblastoma models. These transgenic microRNA clusters display intercellular propagation in vivo, via extracellular vesicles, extending their biological effect throughout the whole tumor. Our results support the rationale and feasibility of combinatorial microRNA strategies for anticancer therapies.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-08390-zTitel-ID: cdi_doaj_primary_oai_doaj_org_article_9eb6fe5b852d43329fafc6511460a696
- Format
- –
- Schlagworte
- Animal models, Animals, Antineoplastic Agents, Alkylating - pharmacology, Biological effects, Brain cancer, Brain Neoplasms - genetics, Brain Neoplasms - mortality, Brain Neoplasms - pathology, Brain Neoplasms - therapy, Cancer, Cell Line, Tumor, Cell Proliferation - drug effects, Cell Proliferation - radiation effects, Chemoradiotherapy, Chemotherapy, Chromatin, Cluster Analysis, Clustering, Combinatorial analysis, Deregulation, Enhancer of Zeste Homolog 2 Protein - genetics, Enhancer of Zeste Homolog 2 Protein - metabolism, Epigenesis, Genetic, Epigenetics, Extracellular Vesicles - chemistry, Extracellular Vesicles - metabolism, Feasibility studies, Female, Gamma Rays - therapeutic use, Gene expression, Gene Expression Regulation, Neoplastic, Gene therapy, Glioblastoma, Glioblastoma - genetics, Glioblastoma - mortality, Glioblastoma - pathology, Glioblastoma - therapy, Histone Demethylases - genetics, Histone Demethylases - metabolism, Humans, Mice, Mice, Nude, MicroRNAs, MicroRNAs - genetics, MicroRNAs - metabolism, miRNA, Neuroglia - drug effects, Neuroglia - metabolism, Neuroglia - pathology, Neuroglia - radiation effects, Polycomb Repressive Complex 1 - genetics, Polycomb Repressive Complex 1 - metabolism, Protein folding, Proteins, Regulators, Repressors, Ribonucleic acid, RNA, Survival, Survival Analysis, Synchronism, Synergism, Temozolomide - pharmacology, Transcription, Tumors, Xenograft Model Antitumor Assays