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FLI1 regulates radiotherapy resistance in nasopharyngeal carcinoma through TIE1-mediated PI3K/AKT signaling pathway
Enni Chen1, Jiajia Huang1, Miao Chen1
1State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
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.
Insights
FLI1 overexpression drives radiotherapy resistance in nasopharyngeal carcinoma (NPC) by upregulating TIE1 and activating the PI3K/AKT pathway. Targeting this FLI1/TIE1 axis may improve NPC treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Radiotherapy resistance is a primary cause of treatment failure and poor prognosis in nasopharyngeal carcinoma (NPC).
- Understanding the molecular mechanisms of radioresistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying radiotherapy resistance in NPC.
- To investigate the role of FLI1 in NPC radiosensitivity and its potential interaction with TIE1.
Main Methods:
- RNA-sequencing was performed on NPC tissues with complete response (CR) versus progressive disease (PD) after radiotherapy.
- In vitro and in vivo loss-and-gain-of-function assays were used to assess FLI1's oncogenic role.
- ChIP and dual luciferase reporter assays were employed to determine the interaction between FLI1 and TIE1.
- Clinical data from NPC tissue microarrays were analyzed to correlate FLI1/TIE1 expression with prognosis.
Main Results:
- FLI1 was significantly overexpressed in NPC patients with PD compared to CR, acting as a radiosensitivity regulator.
- FLI1 promoted radiotherapy resistance and enhanced DNA damage repair in vitro and in vivo.
- FLI1 upregulated TIE1 transcription by binding to its promoter, activating the PI3K/AKT pathway.
- Reduced TIE1 expression restored radiosensitivity in NPC cells, and high FLI1/TIE1 levels correlated with poor prognosis.
Conclusions:
- FLI1 drives NPC radiotherapy resistance via the TIE1-mediated PI3K/AKT signaling pathway.
- The FLI1/TIE1 signaling pathway represents a potential therapeutic target to enhance radiotherapy efficacy in NPC.
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