miR-221/222 Confers Radioresistance in Glioblastoma Cells Through Activating Akt Independent of PTEN Status

Abstract

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.

MicroRNA-590-3p enhances the radioresistance in glioblastoma cells by targeting LRIG1

“…Various miRNAs have been demonstrated to be associated with the radiosensitivity of human glioma cells, such as miR-181a, miR-124 and miR-26a (26)(27)(28)(29)(30). The present results indicate that the expression level of miR-590-3p was higher in the radioresistant human glioblastoma cells than that in the parental glioblastoma cells.…”

Action of HMGB1 on miR-221/222 cluster in neuroblastoma cell lines

“…The present study demonstrated that miR-221 and -222 are more highly expressed in SK-N-BE(2) cells than in SH-SY5Y cells. It is known that the miR-221/222 cluster targets PTEN (21), an oncosuppressor gene that is considered to be one of the primary regulators of AKT-activating pathways. The PTEN gene is frequently lost on chromosome 10q2317 in various types of human cancer.…”

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

“…Обнаружено, что miR-221/222, повышение уровня экспрессии которой неоднократно отмечалось при глиомах, опосредует восстановление повреждений ДНК в клетках глиобластомы, независимо от PTEN, что указывает на её возможность быть потенциальной терапевтической мишенью для увеличения радиочувствительности опухолевых клеток [111]. Гипоксия приводит к увеличению уровня мРНК HIF2A и miR-210 в ОСК глиомы, при этом нокдаун miR-210 снижал способность ОСК глиомы к формированию нейросфер, экспрессию маркеров стволовых клеток, индуцировал дифференцировку и остановку клеточного цикла в фазе G 0 /G 1 [112].…”