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J Neurooncol. 2016 Jul;128(3):395-404. doi: 10.1007/s11060-016-2125-x. Epub 2016 Apr 11.

Shift of microRNA profile upon orthotopic xenografting of glioblastoma spheroid cultures.

Author information

1
Department of Pathology, Odense University Hospital, Winsløwparken 15, 5000, Odense C, Denmark. bo.halle@rsyd.dk.
2
Department of Neurosurgery, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark. bo.halle@rsyd.dk.
3
Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19.3, 5000, Odense C, Denmark. bo.halle@rsyd.dk.
4
Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19.3, 5000, Odense C, Denmark.
5
Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.
6
Regulus Therapeutics, 3545 John Hopkins Ct., Suite 210, San Diego, CA, 92121-1121, USA.
7
Department of Pathology, Odense University Hospital, Winsløwparken 15, 5000, Odense C, Denmark.
8
Department of Neurosurgery, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.
9
Department of Nuclear Medicine, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.
10
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winsløwparken 21, 5000, Odense C, Denmark.
11
Faculty of Health Sciences, Lundbeckfonden Center of Excellence NanoCAN and Molecular Oncology, Institute of Molecular Medicine, University of Southern Denmark, Winsløwparken 25, 5000, Odense C, Denmark.

Abstract

Glioblastomas always recur despite surgery, radiotherapy and chemotherapy. A key player in the therapeutic resistance may be immature tumor cells with stem-like properties (TSCs) escaping conventional treatment. A group of promising molecular targets are microRNAs (miRs). miRs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. In this study we aimed to identify over-expressed TSC-related miRs potentially amenable for therapeutic targeting. We used non-differentiated glioblastoma spheroid cultures (GSCs) containing TSCs and compared these to xenografts using a NanoString nCounter platform. This revealed 19 over-expressed miRs in the non-differentiated GSCs. Additionally, non-differentiated GSCs were compared to neural stem cells (NSCs) using a microarray platform. This revealed four significantly over-expressed miRs in the non-differentiated GSCs in comparison to the NSCs. The three most over-expressed miRs in the non-differentiated GSCs compared to xenografts were miR-126, -137 and -128. KEGG pathway analysis suggested the main biological function of these over-expressed miRs to be cell-cycle arrest and diminished proliferation. To functionally validate the profiling results suggesting association of these miRs with stem-like properties, experimental over-expression of miR-128 was performed. A consecutive limiting dilution assay confirmed a significantly elevated spheroid formation in the miR-128 over-expressing cells. This may provide potential therapeutic targets for anti-miRs to identify novel treatment options for GBM patients.

KEYWORDS:

Cancer stem cell; Glioblastoma; MicroRNA; Tumor stem cell

PMID:
27063952
DOI:
10.1007/s11060-016-2125-x
[Indexed for MEDLINE]

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