Abstract
Current therapies for most non-infectious diseases are directed at or affect functionality of the human translated genome, barely 2% of all genetic information. By contrast, the therapeutic potential of targeting the transcriptome, ~ 70% of the genome, remains largely unexplored. RNA therapeutics is an emerging field that widens the range of druggable targets and includes elements such as microRNA. Here, we sought to screen for microRNA with tumor-suppressive functions in neuroblastoma, an aggressive pediatric tumor of the sympathetic nervous system that requires the development of new therapies. We found miR-323a-5p and miR-342-5p to be capable of reducing cell proliferation in multiple neuroblastoma cell lines in vitro and in vivo, thereby providing a proof of concept for miRNA-based therapies for neuroblastoma. Furthermore, the combined inhibition of the direct identified targets such as CCND1, CHAF1A, INCENP and BCL-XL could reveal new vulnerabilities of high-risk neuroblastoma.
Keywords:
14q32; Cancer therapy; Epigenetics; High-throughput screening; Non-coding RNA; Pediatric cancer.
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation
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Child
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Chromatin Assembly Factor-1 / genetics
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Chromatin Assembly Factor-1 / metabolism
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Female
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Gene Expression Regulation, Neoplastic*
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HEK293 Cells
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High-Throughput Screening Assays
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Humans
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Mice
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Mice, Nude
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Nervous System Neoplasms / genetics*
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Nervous System Neoplasms / mortality
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Nervous System Neoplasms / pathology
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Nervous System Neoplasms / therapy
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Neuroblastoma / genetics*
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Neuroblastoma / mortality
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Neuroblastoma / pathology
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Neuroblastoma / therapy
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Neurons / metabolism
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Neurons / pathology
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Protein Binding
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Signal Transduction
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Survival Analysis
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Tumor Burden
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Xenograft Model Antitumor Assays
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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BCL2L1 protein, human
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CCND1 protein, human
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CHAF1A protein, human
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Chromatin Assembly Factor-1
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Chromosomal Proteins, Non-Histone
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INCENP protein, human
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MIRN323 microRNA, human
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MIRN342 microRNA, human
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MicroRNAs
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bcl-X Protein
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Cyclin D1