title: MiR-338-5p sensitizes glioblastoma cells to radiation through regulation of genes involved in DNA damage response.
abstract: 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.
authors.affiliation: Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Brno, Czech Republic.|Central European Institute of Technology (CEITEC), Masaryk University, University Campus Bohunice, Building A3, Kamenice 5, 625 00, Brno, Czech Republic.
authors.forename: Andrej
authors.initials: A
authors.lastname: Besse
authors.affiliation: Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Brno, Czech Republic.|Central European Institute of Technology (CEITEC), Masaryk University, University Campus Bohunice, Building A3, Kamenice 5, 625 00, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Sana
authors.affiliation: Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Lakomy
authors.affiliation: University Hospital Brno, Department of Pathology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Leos
authors.initials: L
authors.lastname: Kren
authors.affiliation: University Hospital Brno, Department of Neurosurgery, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Fadrus
authors.affiliation: University Hospital Brno, Department of Neurosurgery, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Smrcka
authors.affiliation: First Department of Pathological Anatomy, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Marketa
authors.initials: M
authors.lastname: Hermanova
authors.affiliation: Department of Neurosurgery, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Jancalek
authors.affiliation: Department of Neurosurgery, University Hospital Ostrava, Ostrava, Czech Republic.
authors.forename: Stefan
authors.initials: S
authors.lastname: Reguli
authors.affiliation: Department of Neurosurgery, University Hospital Ostrava, Ostrava, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Lipina
authors.affiliation: Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Svoboda
authors.affiliation: Department of Radiation Oncology, Memorial Cancer Institute, Brno, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Slampa
authors.affiliation: Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, Brno, Czech Republic. on.slaby@gmail.com.|Central European Institute of Technology (CEITEC), Masaryk University, University Campus Bohunice, Building A3, Kamenice 5, 625 00, Brno, Czech Republic. on.slaby@gmail.com.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Slaby
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D000076205:Ras Homolog Enriched in Brain Protein
chemical_list: D002352:Carrier Proteins; C532050:MIRN338 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C451223:NDFIP1 protein, human; D009363:Neoplasm Proteins; D009479:Neuropeptides; C525690:PPP2R5A protein, human; C490211:RHEB protein, human; D012334:RNA, Neoplasm; D000076205:Ras Homolog Enriched in Brain Protein; D054648:Protein Phosphatase 2; D020559:Monomeric GTP-Binding Proteins
keywords: GBM; Glioblastoma multiforme; Radiation resistance; miRNA; miRNA338-5p