Abstract
Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-23a in NPC radioresistance, one of downregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-23a was frequently downregulated in the radioresistant NPC tissues, and its decrement correlated with NPC radioresistance and poor patient survival, and was an independent predictor for reduced patient survival. In vitro radioresponse assays showed that restoration of miR-23a expression markedly increased NPC cell radiosensitivity. In a mouse model, therapeutic administration of miR-23a agomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we found that reduced miR-23a promoted NPC cell radioresistance by activating IL-8/Stat3 signaling. Moreover, the levels of IL-8 and phospho-Stat3 were increased in the radioresistance NPC tissues, and negatively associated with miR-23a level. Our data demonstrate that miR-23a is a critical determinant of NPC radioresponse and prognostic predictor for NPC patients, and its decrement enhances NPC radioresistance through activating IL-8/Stat3 signaling, highlighting the therapeutic potential of miR-23a/IL-8/Stat3 signaling axis in NPC radiosensitization.
Highlights
Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from nasopharyngeal epithelial cells with a remarkable racial and geographical distribution
Using qRT-PCR, we further detected the levels of miR-23a expression in a cohort of NPC tissues, and found that miR-23a expression was significantly decreased in the radioresistant NPCs relative to radiosensitive NPCs (Figure 1A), and negatively correlated with NPC radioresistance (r = −0.715, P < 0.001)
The results revealed that low miR-23a level in the NPC tissues correlated with the markedly reduced disease-free survival (DFS) and overall survival (OS) of the patients (Figure 1C)
Summary
Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from nasopharyngeal epithelial cells with a remarkable racial and geographical distribution. It is highly prevalent in Southern China and Southern Asia, and poses a very serious health problem in these areas [1]. More accurate tumor localization and better RT techniques have contributed to the improvement in the local control of NPC, a major obstacle to achieve long-term survival is radioresistance [2, 3]. The underlying molecular mechanisms of NPC radioresistance remain poorly understood. Regulation of tumor radiosensitivity via miRs-associated mechanisms has attracted much attention in the recent years [5,6,7,8]. Over the past few years, several miRs involving in tumor radioresistance, such as miR-23b [9], miR-95[10], miR21[11], let7 [12], miR-205 [13], miR-210 [14], miR-181a [15], miR-125b [16], and miR-324-3p [17] have been identified
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