DNA Damage and Repair A Functional Screen Identifies miRs That Induce Radioresistance in Glioblastomas

The efficacy of radiotherapy in many tumor types is limited by normal tissue toxicity and by intrinsic or acquired radioresistance. Therefore, it is essential to understand the molecular network responsible for regulating radiosensitivity/resistance. Here, an unbiased functional screen identified four microRNAs (miR1, miR125a, miR150, andmiR425) that induce radioresistance. Considering the clinical importance of radiotherapy for patients with glioblastoma, the impact of thesemiRNAs on glioblastoma radioresistance was investigated.Overexpression of miR1, miR125a, miR150, and/or miR425 in glioblastoma promotes radioresistance through upregulation of the cell-cycle checkpoint response. Conversely, antagonizing with antagomiRs sensitizes glioblastoma cells to irradiation, suggesting their potential as targets for inhibiting therapeutic resistance. Analysis of glioblastoma datasets fromTheCancer GenomeAtlas (TCGA) revealed that thesemiRNAs are expressed in glioblastoma patient specimens and correlate with TGFb signaling. Finally, it is demonstrated that expression ofmiR1 andmiR125a can be induced by TGFb and antagonized by a TGFb receptor inhibitor. Together, these results identify and characterize a new role formiR425,miR1,miR125, andmiR150 in promoting radioresistance in glioblastomas and provide insight into the therapeutic application of TGFb inhibitors in radiotherapy. Implications: Systematic identification of miRs that cause radioresistance in gliomas is important for uncovering predictive markers for radiotherapy or targets for overcoming radioresistance. Mol Cancer Res; 12(12); 1767–78. 2014 AACR.