Shift of microRNA profile upon orthotopic xenografting of glioblastoma spheroid cultures

Bo Halle, Mads Thomassen, Ranga Venkatesan, Vivek Kaimal, Eric G Marcusson, Sune Munthe, Mia D Sørensen, Charlotte Aaberg-Jessen, Stine S Jensen, Morten Meyer, Torben A Kruse, Helle Christiansen, Steffen Schmidt, Jan Mollenhauer, Mette K Schulz, Claus Andersen, Bjarne W Kristensen

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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.

TidsskriftJournal of Neuro-Oncology
Udgave nummer3
Sider (fra-til) 395–404
StatusUdgivet - 11. apr. 2016

Bibliografisk note

First online: 11 April 2016


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