miR-221/222 confers radioresistance in glioblastoma cells through activating Akt independent of PTEN status.

Glioblastoma is highly resistant to radiation therapy. The underlying molecular mechanism is not completely understood. The DNA damage response (DDR) pathway plays a crucial role in radioresistance of glioablastoma cells. Growing evidence has demonstrated that radiation induces alterations in microRNA (miR) profiles. However, how radiation induces specific miRs and how they might regulate the DDR remain elusive. In our study, we found that radiation induced c-jun transcription of miR-221 and miR-222. miR-221 and miR- 222 modulated DNA-PKcs expression to affect DNA damage repair by activating Akt independent of PTEN status. Knocking down of miR-221/222 significantly increased radiosensitivity of glioblastoma cells. Inhibition of Akt by RNAi or LY294002 treatment may overcome miR-221/222 induced radioresistance. Notably, combined anti-miR-221/222 and radiotherapy has remarkably inhibited tumor growth compared with anti-miR-221/222 or radiotherapy alone in a subcutaneous mouse model. Our results suggest that radio-induced c-jun promotes transcription of miR-221/222, which mediates DNA damage repair of glioblastoma cells independent of PTEN. These data indicate for the first time that miR-221/222 play an important role in mediating radio-induced DNA damage repair and that miR-221/222 could serve as potential therapeutic targets for increasing radiosensitivity of glioblastoma cells.