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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
Author(s) -
Krell A.,
Wolter M.,
Stojcheva N.,
Hertler C.,
Liesenberg F.,
Zapatka M.,
Weller M.,
Malzkorn B.,
Reifenberger G.
Publication year - 2019
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12532
Subject(s) - glioma , cancer research , cyclin dependent kinase 6 , temozolomide , biology , apoptosis , trichostatin a , cell cycle , gene knockdown , microrna , cell cycle checkpoint , cell growth , mcl1 , microbiology and biotechnology , downregulation and upregulation , cyclin d1 , histone deacetylase , biochemistry , gene , histone , genetics
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 (TSA) 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 (TMZ) 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. TSA 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 TMZ. Conclusion Reduced expression of miR‐16‐5p contributes to glioma cell proliferation, survival and resistance to cytotoxic therapy.