MiR-338-5p sensitizes glioblastoma cells to radiation through regulation of genes involved in DNA damage response
- 512 Downloads
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.
KeywordsGlioblastoma multiforme GBM Radiation resistance miRNA miRNA338-5p
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
- 10.Lim YC, Roberts TL, Day BW, Stringer BW, Kozlov S, Fazry S, Bruce ZC, Ensbey KS, Walker DG, Boyd AW, Lavin MF. Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells. Mol Oncol. 2014Google Scholar
- 17.Liu C, Wang Z, Wang Y, Gu W. Mir-338 suppresses the growth and metastasis of OSCC cells by targeting nrp1. Mol Cell Biochem. 2014Google Scholar
- 23.Manning BD, Cantley LC. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci. 28:573–6.Google Scholar
- 25.Low LH, Chow YL, Li Y, Goh CP, Putz U, Silke J, et al. Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during the DNA damage response. J Biol Chem. 2015;290:7141–50.CrossRefPubMedPubMedCentralGoogle Scholar