Glioblastoma stem-like cells (GSCs) are critical for the aggressiveness and progression of glioblastoma (GBM) and contribute to its resistance to adjuvant treatment. MicroRNAs (miRNAs) are small, non-coding RNAs controlling gene expression at the post-transcriptional level, which are known to be important regulators of the stem-like features. Moreover, miRNAs have been previously proved to be promising diagnostic biomarkers in several cancers including GBM. Using global expression analysis of miRNAs in 10 paired in-vitro as well as in-vivo characterized primary GSC and non-stem glioblastoma cultures, we identified a miRNA signature associated with the stem-like phenotype in GBM. 51 most deregulated miRNAs classified the cell cultures into GSC and non-stem cell clusters and identified a subgroup of GSC cultures with more pronounced stem-cell characteristics. The importance of the identified miRNA signature was further supported by demonstrating that a Risk Score based on the expression of seven miRNAs overexpressed in GSC predicted overall survival in GBM patients in the TCGA dataset independently of the IDH1 status. In summary, we identified miRNAs differentially expressed in GSCs and described their association with GBM patient survival. We propose that these miRNAs participate on GSC features and could represent helpful prognostic markers and potential therapeutic targets in GBM.

• MeSH
• analýza přežití MeSH
• glioblastom genetika   MeSH
• isocitrátdehydrogenasa genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• mutace MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové buňky kultivované MeSH
• nádorové kmenové buňky chemie   MeSH
• nádory mozku genetika   MeSH
• nestin MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• stanovení celkové genové exprese metody   MeSH
• transkripční faktory SOXB1 genetika   MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• IDH1 protein, human MeSH Prohlížeč
• isocitrátdehydrogenasa MeSH
• mikro RNA MeSH
• NES protein, human MeSH Prohlížeč
• nestin MeSH
• SOX2 protein, human MeSH Prohlížeč
• transkripční faktory SOXB1 MeSH

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. Despite radical surgery and radiotherapy supported by chemotherapy, the disease still remains incurable with an extremely low median survival rate of 12-15 months from the time of initial diagnosis. The main cause of treatment failure is considered to be the presence of cells that are resistant to the treatment. MicroRNAs (miRNAs) as regulators of gene expression are involved in the tumor pathogenesis, including GBM. MiR-338 is a brain-specific miRNA which has been described to target pathways involved in proliferation and differentiation. In our study, miR-338-3p and miR-338-5p were differentially expressed in GBM tissue in comparison to non-tumor brain tissue. Overexpression of miR-338-3p with miRNA mimic did not show any changes in proliferation rates in GBM cell lines (A172, T98G, U87MG). On the other hand, pre-miR-338-5p notably decreased proliferation and caused cell cycle arrest. Since radiation is currently the main treatment modality in GBM, we combined overexpression of pre-miR-338-5p with radiation, which led to significantly decreased cell proliferation, increased cell cycle arrest, and apoptosis in comparison to irradiation-only cells. To better elucidate the mechanism of action, we performed gene expression profiling analysis that revealed targets of miR-338-5p being Ndfip1, Rheb, and ppp2R5a. These genes have been described to be involved in DNA damage response, proliferation, and cell cycle regulation. To our knowledge, this is the first study to describe the role of miR-338-5p in GBM and its potential to improve the sensitivity of GBM to radiation.

• Klíčová slova
• GBM, Glioblastoma multiforme, Radiation resistance, miRNA, miRNA338-5p,
• MeSH
• buněčné dělení účinky léků   účinky záření   MeSH
• glioblastom genetika   patologie   MeSH
• kontrolní body buněčného cyklu účinky léků   účinky záření   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny biosyntéza   genetika   MeSH
• mikro RNA genetika   MeSH
• monomerní proteiny vázající GTP biosyntéza   genetika   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• nádory mozku genetika   patologie   MeSH
• neuropeptidy biosyntéza   genetika   MeSH
• poškození DNA genetika   MeSH
• protein Rheb MeSH
• proteinfosfatasa 2 biosyntéza   genetika   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• RNA nádorová genetika   MeSH
• stanovení celkové genové exprese MeSH
• tolerance záření genetika   MeSH
• transportní proteiny biosyntéza   genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové proteiny MeSH
• mikro RNA MeSH
• MIRN338 microRNA, human MeSH Prohlížeč
• monomerní proteiny vázající GTP MeSH
• nádorové proteiny MeSH
• NDFIP1 protein, human MeSH Prohlížeč
• neuropeptidy MeSH
• PPP2R5A protein, human MeSH Prohlížeč
• protein Rheb MeSH
• proteinfosfatasa 2 MeSH
• RHEB protein, human MeSH Prohlížeč
• RNA nádorová MeSH
• transportní proteiny MeSH