胶质瘤干细胞（GSCs）放疗抵抗是胶质瘤复发和治疗失败的重要原因。基于肿瘤细胞低剂量放疗超敏现象，我们建立新的放疗方法、低剂量超微分割放疗(ld-UmRT)，即采用0.2Gy超微分割，每个超微分割间隔3分钟。前期研究结果显示ld-UmRT显著增强对GSCs杀伤作用。基于EGFR-Akt-PKcs信号通路在DNA双链断裂修复、细胞存活中的关键作用，结合我们前期发现GSCs表达EGFRvⅢ和ld-UmRT后GSCs内PKcs活化受抑的证据，推测EGFRvⅢ-Akt-PKcs途径在ld-UmRT克服GSCs放疗抵抗中起重要作用。拟通过体内外实验观察：GSCs在ld-UmRT后EGFRvⅢ-Akt-PKcs信号通路表达、活化；干预该信号通路后对GSCs在ld-UmRT及常规放疗后损伤效应变化。通过本研究，不但有利于完善GSCs放疗抵抗的分子机制，也将为ldUmRT特异性杀伤GSCs应用提供理论依据

Radiotherapy is the most effective nonsurgical treatment modality yet recurrence is essentially universal. Glioblastoma stem cells (GSCs), which was able to initiate or reconstitue tumor, is highly resistant to irradiation. The survival of GSCs play an important role on recurrence of glioma. The phenomena of low-dose hyper-radiosensitivity were seen in several tumor cells. A low-dose-rate ultra-microfraction (ld-UmRT) of radiotherapy was used to treat the GSCs by us. The daily fractions of 2 Gy were divided to 10 ultra-microfractions and every 0.2 Gy ultra-microfraction separated by 3 min time intervals. Then, the dose rate of 4~6 Gy/min was created to a low-dose-rate of 0.07 Gy/min. The survival rate decreased significant in GSCs after ld-UmRT compared to conventional radiotherapy in vitro. The most lethal among radiation-induced DNA lesions is the double-strand break (DSB). DSB repair is critical for cell survival after radiation induced DSB. There are data suggesting that EGFR-Akt-PKcs signaling pathways played an important role in radiosensitivity of tumor cell such as glioma cell and so on. We found that EGFRvⅢ was expressed in GSCs and the active of PKcs was inhibited in GSCs after GSCs received ld-UmRT. Therefore, We hypothesis that the DSB repair of GSCs depended on EGFRvⅢ/Akt/PKcs signaling pathways and this pathways was inhibited by ld-UmRT in GSCs. The EGFRvⅢ/Akt/PKcs signaling pathways will be tested in GSCs after ld-UmRT and the effect of ld-UmRT or conventional radiotherapy on blockage of EGFRvⅢ/Akt/PKcs signaling pathways in GSCs will be observed in our future work. The results of this study will help us to understand the mechanism of ld-UmRT increasing damage in GSCs.