Radiotherapy resistance is the main cause of treatment failure in nasopharyngeal carcinoma (NPC), which leads to poor prognosis. It is urgent to elucidate the molecular mechanisms underlying radiotherapy resistance. Here we identified FLI1 as a potential radiosensitivity regulator which was dramatically overexpressed in the patients with progressive disease (PD) to radiotherapy compared to those with complete response (CR). We examined the effect of FLI1 on cell survival, apoptosis and γ-H2AX expression in NPC cells after radiation, and found that FLI1 induced radiotherapy resistance and enhanced the ability of DNA damage repair in NPC cells. We also confirmed the role of FLI1 in regulating radiotherapy resistance in vivo using the nude mouse NPC xenograft model. Moreover, we demonstrated that FLI1 upregulated the transcription of TIE1 by binding to its promoter. The rescue experiment further confirmed that FLI1 activated the PI3K/AKT signaling pathway by upregulating TIE1, thereby affecting radiotherapy sensitivity of NPC cells. Furthermore, we showed that NPC patients with high levels of FLI1 and TIE1 were correlated with poor prognosis. Together, our study has revealed that FLI1 regulates radiotherapy resistance of NPC through TIE1-mediated PI3K/AKT signaling pathway, suggesting that targeting the FLI1/TIE1 signaling pathway could be a potential therapeutic strategy to enhance the efficacy of radiotherapy in NPC.

Background Radiotherapy resistance is the main cause of treatment failure in nasopharyngeal carcinoma (NPC), which leads to poor prognosis. It is urgent to elucidate the molecular mechanisms underlying radiotherapy resistance. Methods RNA-seq analysis was applied to five paired progressive disease (PD) and complete response (CR) NPC tissues. Loss-and gain-of-function assays were used for oncogenic function of FLI1 both in vitro and in vivo. RNA-seq analysis, ChIP assays and dual luciferase reporter assays were performed to explore the interaction between FLI1 and TIE1. Gene expression with clinical information from tissue microarray of NPC were analyzed for associations between FLI1/TIE1 expression and NPC prognosis. Results FLI1 is a potential radiosensitivity regulator which was dramatically overexpressed in the patients with PD to radiotherapy compared to those with CR. FLI1 induced radiotherapy resistance and enhanced the ability of DNA damage repair in vitro, and promoted radiotherapy resistance in vivo. Mechanistic investigations showed that FLI1 upregulated the transcription of TIE1 by binding to its promoter, thus activated the PI3K/AKT signaling pathway. A decrease in TIE1 expression restored radiosensitivity of NPC cells. Furthermore, NPC patients with high levels of FLI1 and TIE1 were correlated with poor prognosis. Conclusion Our study has revealed that FLI1 regulates radiotherapy resistance of NPC through TIE1-mediated PI3K/AKT signaling pathway, suggesting that targeting the FLI1/TIE1 signaling pathway could be a potential therapeutic strategy to enhance the efficacy of radiotherapy in NPC.