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Tumor Biology

, Volume 37, Issue 6, pp 7719–7727 | Cite as

MiR-338-5p sensitizes glioblastoma cells to radiation through regulation of genes involved in DNA damage response

  • Andrej Besse
  • Jiri Sana
  • Radek Lakomy
  • Leos Kren
  • Pavel Fadrus
  • Martin Smrcka
  • Marketa Hermanova
  • Radim Jancalek
  • Stefan Reguli
  • Radim Lipina
  • Marek Svoboda
  • Pavel Slampa
  • Ondrej Slaby
Original Article

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.

Keywords

Glioblastoma multiforme GBM Radiation resistance miRNA miRNA338-5p 

Notes

Acknowledgments

This work was supported by grants NT13514-4/2012 and NT13581-4/2012 of the Czech Ministry of Health, the project “CEITEC–Central European Institute of Technology” (CZ.1.05/1.1.00/02.0068), and the project MZ CR–RVO (MOU, 00209805).

Compliance with ethical standards

Informed consent was obtained from each patient before the treatment.

Conflicts of interest

None

Supplementary material

13277_2015_4654_MOESM1_ESM.docx (179 kb)
ESM 1 (DOCX 179 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Andrej Besse
    • 1
    • 2
  • Jiri Sana
    • 1
    • 2
  • Radek Lakomy
    • 1
  • Leos Kren
    • 3
  • Pavel Fadrus
    • 4
  • Martin Smrcka
    • 4
  • Marketa Hermanova
    • 5
  • Radim Jancalek
    • 6
  • Stefan Reguli
    • 7
  • Radim Lipina
    • 7
  • Marek Svoboda
    • 1
  • Pavel Slampa
    • 8
  • Ondrej Slaby
    • 1
    • 2
  1. 1.Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  2. 2.Central European Institute of Technology (CEITEC)Masaryk UniversityBrnoCzech Republic
  3. 3.University Hospital Brno, Department of Pathology, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  4. 4.University Hospital Brno, Department of Neurosurgery, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  5. 5.First Department of Pathological Anatomy, St. Anne’s University Hospital and Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  6. 6.Department of Neurosurgery, St. Anne’s University Hospital and Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  7. 7.Department of NeurosurgeryUniversity Hospital OstravaOstravaCzech Republic
  8. 8.Department of Radiation OncologyMemorial Cancer InstituteBrnoCzech Republic

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