FLI1 regulates radiotherapy resistance in nasopharyngeal carcinoma through TIE1-mediated PI3K/AKT signaling pathway

Abstract

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.

Identification of the Expression of TIE1 and Its Mediated Immunosuppression in Gastric Cancer

“…More and more literature has demonstrated aberrant expression of TIE1 in diverse tumor types, with several studies indicating its potential role in promoting carcinogenesis and tumor progression. For example, breast cancer, colorectal cancer, nasopharyngeal carcinoma, to name a few 8 , 12 , 30 .…”

“…TIE1 (tyrosine kinase with immunoglobulin-like and EGF-like domains 1) is a tyrosine kinase receptor, originally found in an erythroleukemia cell line 7 , 8 . Previous research has shown that TIE1 is primarily expressed in endothelial cells and plays a crucial role in the formation of blood and lymphatic vessels 9 .…”

TRAF4 regulates ubiquitination-modulated survivin turnover and confers radioresistance

“…Radiotherapy plays a vital role in treating nasopharyngeal carcinoma 4 . Despite technological advances, the prognosis of NPC patients after radiotherapy varies widely 39 , possibly related to the development of radioresistance 40 .…”

“…Genetic, viral, and dietary factors are implicated in the tumorigenesis of NPC 2 . Intensity-modulated radiotherapy is currently the primary management for NPC because of the radiosensitivity and complicated anatomic construction 3 , 4 . Although clinical treatment strategies are continuously advanced, partial patients exhibit unusual radioresistance, resulting in failure in therapy 5 .…”