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MiR-16-5p is frequently down-regulated in astrocytic gliomas and modulates glioma cell proliferation, apoptosis, and response to cytotoxic therapy


Krell, Anneliese; Wolter, Marietta; Stojcheva, Nina; Hertler, Caroline; Liesenberg, Franziska; Zapatka, Marc; Weller, Michael; Malzkorn, Bastian; Reifenberger, Guido (2019). MiR-16-5p is frequently down-regulated in astrocytic gliomas and modulates glioma cell proliferation, apoptosis, and response to cytotoxic therapy. Neuropathology and Applied Neurobiology, 45(6):441-458.

Abstract

AIMS
Aberrant expression of microRNAs (miRNAs) is frequent in various cancers including gliomas. We aimed to characterize the role of miR-16-5p as a candidate tumour suppressor miRNA in gliomas.
METHODS
Real-time PCR-based approaches were used for miRNA and mRNA expression profiling of glioma and non-neoplastic brain tissues as well as glioma cell lines. Protein levels were determined by Western blotting. In vitro analyses were performed following overexpression of miR-16-5p, trichostatin A treatment, and siRNA-mediated knock-down of HDAC3 in glioma cells. Effects of miR-16-5p on glioma cell viability, apoptosis and response to irradiation and temozolomide were assessed.
RESULTS
Expression of miR-16-5p was reduced relative to control brain tissue in isocitrate dehydrogenase (IDH)-mutant astrocytomas of World Health Organization (WHO) grades II, III, and IV, and a subset of IDH-wildtype glioblastomas WHO grade IV. MiR-16-5p expression was lower in IDH-mutant than in IDH-wildtype gliomas, and down-regulated in IDH-wildtype glioma lines. MiR-16-5p overexpression reduced expression of important cell cycle and apoptosis regulators in glioma cells, including CDK6, CDC25A, CCND3, CCNE1, WEE1, CHEK1, BCL2, and MCL1. In line, CDK6, WEE1, CHEK1, BCL2, and MCL1 transcript levels were increased in WHO grade III or IV gliomas. Trichostatin A treatment and HDAC3 knockdown in glioma cells induced miR-16-5p up-regulation and reduced expression of its targets. Moreover, miR-16-5p overexpression inhibited proliferation and induced apoptosis in various glioma cell lines and increased sensitivity of A172 glioma cells to irradiation and temozolomide.
CONCLUSION
Reduced expression of miR-16-5p contributes to glioma cell proliferation, survival, and resistance to cytotoxic therapy. This article is protected by copyright. All rights reserved.

Abstract

AIMS
Aberrant expression of microRNAs (miRNAs) is frequent in various cancers including gliomas. We aimed to characterize the role of miR-16-5p as a candidate tumour suppressor miRNA in gliomas.
METHODS
Real-time PCR-based approaches were used for miRNA and mRNA expression profiling of glioma and non-neoplastic brain tissues as well as glioma cell lines. Protein levels were determined by Western blotting. In vitro analyses were performed following overexpression of miR-16-5p, trichostatin A treatment, and siRNA-mediated knock-down of HDAC3 in glioma cells. Effects of miR-16-5p on glioma cell viability, apoptosis and response to irradiation and temozolomide were assessed.
RESULTS
Expression of miR-16-5p was reduced relative to control brain tissue in isocitrate dehydrogenase (IDH)-mutant astrocytomas of World Health Organization (WHO) grades II, III, and IV, and a subset of IDH-wildtype glioblastomas WHO grade IV. MiR-16-5p expression was lower in IDH-mutant than in IDH-wildtype gliomas, and down-regulated in IDH-wildtype glioma lines. MiR-16-5p overexpression reduced expression of important cell cycle and apoptosis regulators in glioma cells, including CDK6, CDC25A, CCND3, CCNE1, WEE1, CHEK1, BCL2, and MCL1. In line, CDK6, WEE1, CHEK1, BCL2, and MCL1 transcript levels were increased in WHO grade III or IV gliomas. Trichostatin A treatment and HDAC3 knockdown in glioma cells induced miR-16-5p up-regulation and reduced expression of its targets. Moreover, miR-16-5p overexpression inhibited proliferation and induced apoptosis in various glioma cell lines and increased sensitivity of A172 glioma cells to irradiation and temozolomide.
CONCLUSION
Reduced expression of miR-16-5p contributes to glioma cell proliferation, survival, and resistance to cytotoxic therapy. This article is protected by copyright. All rights reserved.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Pathology and Forensic Medicine
Health Sciences > Histology
Life Sciences > Neurology
Health Sciences > Neurology (clinical)
Health Sciences > Physiology (medical)
Language:English
Date:2019
Deposited On:30 Oct 2019 14:35
Last Modified:01 Aug 2020 00:02
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0305-1846
OA Status:Green
Publisher DOI:https://doi.org/10.1111/nan.12532
PubMed ID:30548945

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