lncRNA n373932/FOXM1环促进鼻咽癌细胞“干性”维持和放疗抵抗的机制研究

Cancer stem cells (CSCs) is a hot field in the research of radioresistance. Our previous results demonstrated that lncRNA n373932 and FOXM1 enhanced the radioresistance of nasopharyngeal carcinoma (NPC) in vitro. Meantime, lncRNA n373932 increased the expression of transcription factor FOXM1 and FOXM1 also elevated the expression of lncRNA n373932, which indicates a lncRNA n373932/FOXM1 regulating loop. Therefore, we hypothesize that lncRNA n373932/FOXM1 loop is critical and indispensable in the maintenance of NPC stemness and promotes its radioresistance. To confirm this hypothesis, we will change the expression of lncRNA n373932 and/or FOXM1 to clarify the role of lncRNA n373932/FOXM1 loop in the regulation of NPC stemness and radioresistance. Our previous data also showed that lncRNA n373932 activated the Hedgehog signaling pathway. Together with the data of bioinformatic analysis, we will try to confirm that whether lncRNA n373932 increases the expression of FOXM1 via the Hedgehog signaling pathway, and whether transcription factor FOXM1 can promote the expression of lncRNA n373932 via increase the promoter activity of lncRNA n373932. Finally, the significance of lncRNA n373932 and FOXM1 will be examined in NPC specimens with intact clinical information. The success of this project will facilitate us to discover valuable molecular biomarkers and therapeutic targets associated with radioresistance in NPC.

肿瘤干细胞在放疗抵抗中的作用备受关注。前期体外研究发现lncRNA n373932和FOXM1均能促进鼻咽癌细胞“干性”和放疗抵抗。lncRNA n373932与FOXM1可相互促进对方表达。据此，我们推测lncRNA n373932和FOXM1可形成调控环路，共同促进鼻咽癌细胞“干性”维持和放疗抵抗。为此，我们首先经功能获得及缺失实验，从体内外阐明lncRNA n373932/FOXM1环在鼻咽癌细胞“干性”维持和放疗抵抗中的作用。结合信息学分析和前期研究发现lncRNA n373932可激活Hedgehog通路，机制研究中将明确lncRNA n373932可经Hedgehog通路转录激活FOXM1，而FOXM1作为转录因子可增强lncRNA n373932启动子活性促进其表达。最后在大样本组织中证实其临床价值。该项目的成功实施，有助于找寻到鼻咽癌放疗抵抗密切相关的分子标志物和干预靶点。

鼻咽癌首选治疗为放疗，但放疗抵抗性的产生严重制约鼻咽癌预后。肿瘤干细胞与放疗抵抗密切相关。本项目在前期基础上，探讨lncRNA n373932/FOXM1环促进鼻咽癌细胞“干性”维持和放疗抵抗的分子机制。我们首先揭示了鼻咽癌放疗抵抗形成过程中肿瘤“干性”增强，通过生物信息学及功能学实验证实lncRNA n373932与FOXM1在鼻咽癌放疗抵抗及“干性”维持中的作用，证实了lncRNA n373932与干性调控基因FOXM1的相互作用，同时探索了放疗抵抗的其他相关分子功能和机制。本项目为鼻咽癌放疗抵抗机制研究提供新的理论依据和实验基础，对其他恶性肿瘤的放疗抵抗性研究亦有借鉴价值。