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.

MicroRNAs for the Prediction of Early Response to Sorafenib Treatment in Human Hepatocellular Carcinoma

“…Previous reports suggest that the plasma level of miR-338-5p is higher in HCC patients than in healthy controls [24]. On the other hand, the expression of pre-miR-338-5p induced a decrease in cell proliferation and cell cycle arrest in glioblastoma cells; miR-338-5p sensitizes tumors to radiation through regulation of genes involved in DNA damage response [25]. Our result suggested that miR-338-5p might have a role in the induction of tumor response to sorafenib treatment, although the quantification of serum miR-338-5p is unstable compared to that of miR-181a-5p because of a lower level of the initial copy number.…”

MicroRNAs Involvement in Radioresistance of Head and Neck Cancer

“…In glioblastoma, miR-128a, miR-135b, miR-1, miR-125a, miR-150, and miR-425 were found to be associated with radioresistance [67–69]. Moreover, our recent study suggests that miR-338-5p sensitizes glioblastoma cells to radiation through regulation of genes involved in DNA damage response such as NDFIP1 (Nedd4 Family Interacting Protein 1), RHEB (RAS homolog enriched in brain), and PPP2R5A (Protein Phosphatase 2 Regulatory Subunit B′, Alph) [70]. In lung cancer loss of miR-1323 and/or miR-18a enhances radiosensitivity whereas miR-511 has been found to suppress growth of radioresistant cell lines [71–73].…”

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Детекция и определение количеств ряда видов микро-РНК в тканях и сыворотке крови онкологических больных может иметь диагностическую и прогностическую значимость. Микро-РНК могут также использоваться для прогнозирования ответа конкретного пациента на терапию (например, miR-338-5p сенсибилизирует клетки глиобластомы к воздействию ионизирующего излучения через регуляцию генов, вовлечённых в ответ на повреждение ДНК) [27,146].…”