Radiation-Induced Micro-RNA Modulation in Glioblastoma Cells Differing in DNA-Repair Pathways

Abstract

Human glioblastomas often develop resistance to radiation therapy. The molecular details of this phenomenon are not completely understood. Recent studies have suggested that deficiency in DNA repair pathways may alter the resistance to ionizing radiation in gliobastomas. The human glioma cell line M059J is deficient in DNA-dependent protein kinase (DNA-PK), whereas cell line M059K, isolated from the same malignant tumor, has normal DNA-PK activity. DNA-PK plays a central role in the repair of ionizing-radiation-induced double-strand break repair, and its deficiency has been correlated with ionizing radiation sensitivity in these glioblastoma cells. We argued that other cellular pathways could also play a role in the resistance to radiation therapy in gliomas. We hypothesized that micro-RNAs (miRNAs) are differentially modulated in M059J and M059K cells exposed to ionizing radiation and that the miRNA modulation contributes to the resistance to ionizing radiation. miRNAs are small nonprotein coding single-stranded RNA molecules, which are crucial posttranscriptional regulators of gene expression. Numerous studies have documented the participation of miRNAs in a wide range of biological processes. The contribution of miRNAs in mediating resistance of glioblastoma cell to ionizing radiation treatment has not been elucidated. To test this hypothesis, we examined the expression patterns of a number of miRNAs involved in carcinogenesis in irradiated M059J and M059K cells. The relative expression level as determined by real-time quantitative PCR for miRNAs belonging to the let-7 family indicated an upregulation in irradiated M059K cells. On the contrary, the analysis of irradiated M059J cells for the modulation of let-7 family of miRNAs revealed an overall downregulation. The miR-17-3p, miR-17-5p, miR-19a, miR-19b, miR-142-3p, and miR-142-5p were upregulated in both M059K and M059J cells. The miR-15a, miR-16, miR-143, miR-155, and miR-21 were upregulated in M059K, and the modulation of these miRNAs fluctuated in M059J cells in a time-dependent manner. These results indicate the involvement of miRNAs in the differential response of glioblastoma cells to ionizing radiation treatment.

The emerging role of miR‐19 in glioma

“…However, research on the relationship between miR‐19 and radiotherapy in glioma is limited. Chaudhry has reported that miR‐19 is up‐regulated in both irradiated glioma cell line M059J which is deficient in DNA‐PK (DNA‐dependent protein kinase) and glioma cell line M059K with normal DNA‐PK activity, indicating that miR‐19 paritcipates in the reaction of different types of glioma cell lines to ionizing radiation 63. Some of the target genes of miR‐19 are related to the radiosensitivity of glioma cells.…”

MicroRNAs and Their Impact on Radiotherapy for Cancer

“…Significantly, certain miRNAs have been identified to consistently show characteristic changes postirradiation across a range of different cancers. For example, expression of several members of the let-7 family, a well-known tumor suppressor and regulator of the K-Ras oncogene, were found to be affected by radiation exposure (29,30,(32)(33)(34)(35). Most members of the let-7 family (except let-7g) have been found to be downregulated in irradiated fibroblasts (33), lung cancer cells (30) or colon cancer cells (35).…”

“…Most members of the let-7 family (except let-7g) have been found to be downregulated in irradiated fibroblasts (33), lung cancer cells (30) or colon cancer cells (35). However, in irradiated glioma and squamous cell carcinoma cell lines REVIEW some members of the let-7 family are upregulated (29,34). Another two miRNAs, miR-21 and miR-34, are consistently upregulated in various benign and malignant cell lines after irradiation (28, 34, 36-38).…”

Time, Dose and Ataxia Telangiectasia Mutated (ATM) Status Dependency of Coding and Noncoding RNA Expression after Ionizing Radiation Exposure

“…This published finding inspired the search for other radiation-responsive miRNAs (19)(20)(21)(22). The radiation-induced miRNA response depends on radiation dose, time post exposure, genetic background (23)(24)(25)(26), the tissue being investigated and gender (27)(28)(29).…”