Radiation resistance poses a major clinical challenge in cancer treatment, but little is known about how microRNA (miR) may regulate this phenomenon. In this study, we used next-generation sequencing to perform an unbiased comparison of miR expression in PC3 prostate cancer cells rendered resistant to fractionated radiation treatment. One miR candidate found to be upregulated by ionizing radiation was miR-95, the enforced expression of which promoted radiation resistance in a variety of cancer cells. miR-95 overexpression recapitulated an aggressive phenotype including increased cellular proliferation, deregulated G 2 -M checkpoint following ionizing radiation, and increased invasive potential. Using combined in silico prediction and microarray expression analyses, we identified and validated the sphingolipid phosphatase SGPP1, an antagonist of sphingosine-1-phosphate signaling, as a target of miR-95 that promotes radiation resistance. Consistent with this finding, cell treatment with FTY720, a clinically approved small molecule inhibitor of S1P signaling, sensitized miR-95 overexpressing cells to radiation treatment. In vivo assays extended the significance of these results, showing that miR-95 overexpression increased tumor growth and resistance to radiation treatment in tumor xenografts. Furthermore, reduced tumor necrosis and increased cellular proliferation were seen after radiation treatment of miR-95 overexpressing tumors compared with control tumors. Finally, miR-95 expression was increased in human prostate and breast cancer specimens compared with normal tissue. Together, our work reveals miR-95 expression as a critical determinant of radiation resistance in cancer cells. Cancer Res; 73(23); 6972-86. Ó2013 AACR.

At least half of all cancer patients will receive radiation therapy. Tumour radioresistance, or the failure to control certain tumours with this treatment, can result in locoregional recurrence; thus there is great interest in understanding the underlying biology and developing strategies to overcome this problem. The expanding investigation of microRNA in cancer suggests that these regulatory factors can influence the DNA damage response, the microenvironment and survival pathways, among other processes, and thereby may affect tumour radioresistance. As microRNA are readily detectable in tumours and biofluids, they hold promise as predictive biomarkers for therapy response and prognosis. This review highlights the current insights on the major ways that microRNA may contribute to tumour radiation response and whether their levels reflect treatment success. We conclude by applying the potential framework of future roles of miR in personalised radiotherapy using prostate cancer clinical management as an example.