BACKGROUND Circular RNAs (circRNAs), a new type of noncoding RNA (ncRNA), have been identified as significant gene expression regulators and are involved in cancer progression. However, the roles of circRNAs in nasopharyngeal carcinoma (NPC) remain largely unknown. METHODS Here, the expression profile of circRNAs in a pair of NPC cell lines with different metastatic abilities (S18 and S26 cells) was analyzed by RNA-sequencing. Quantitative reverse transcription PCR was used to detect the expression level of circCRIM1 in NPC cells and tissues. Then, function experiments in vitro and in vivo were performed to evaluate the effects of circCRIM1 on NPC metastasis and EMT. Mechanistically, RNA immunoprecipitation, luciferase reporter assay, pull-down assay with biotinylated miRNA, fluorescent in situ hybridization were performed to confirm the interaction between circCRIM1 and miR-422a in NPC. The clinical value of circCRIM1 was evaluated in NPC metastasis and chemosensitivity. RESULTS We identified that circCRIM1 was upregulated in highly metastatic NPC cells. CircCRIM1 was also overexpressed in NPC tissues with distant metastasis, and its overexpression promoted NPC cell metastasis and EMT. Mechanistically, circCRIM1 competitively bound to miR-422a and prevented the suppressive effects of miR-422a on its target gene FOXQ1, which finally led to NPC metastasis, EMT and docetaxel chemoresistance. Furthermore, high circCRIM1 expression was associated with unfavorable survival in NPC patients. We established a prognostic model based on circCRIM1 expression and N stage that effectively predicted the risk of distant metastasis and treatment response to docetaxel-containing induction chemotherapy in NPC patients. CONCLUSIONS Our findings reveal the critical role of circCRIM1 specifically in promoting NPC metastasis and chemoresistance via a ceRNA mechanism and provide an exploitable biomarker and therapeutic target for prognosis and treatment resistance in NPC patients.

中文翻译：

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环状RNA CRIM1通过上调FOXQ1作为ceRNA促进鼻咽癌转移和多西他赛化学耐药。

背景技术环状RNA（circRNA），一种新型的非编码RNA（ncRNA），已经被鉴定为重要的基因表达调节剂，并且参与了癌症的发展。但是，circRNA在鼻咽癌（NPC）中的作用仍然未知。方法在这里，通过RNA测序分析了circRNA在一对具有不同转移能力的NPC细胞系（S18和S26细胞）中的表达情况。定量逆转录PCR用于检测circCRIM1在NPC细胞和组织中的表达水平。然后，进行体外和体内功能实验，以评估circCRIM1对NPC转移和EMT的影响。从机理上讲，RNA免疫沉淀，荧光素酶报告基因分析，生物素化miRNA的下拉分析，进行荧光原位杂交以确认circCRIM1和miR-422a在NPC中的相互作用。在NPC转移和化学敏感性中评估了circCRIM1的临床价值。结果我们发现在高度转移的NPC细胞中circCRIM1被上调。CircCRIM1在具有远处转移的NPC组织中也过表达，其过表达促进了NPC细胞的转移和EMT。从机制上讲，circCRIM1与miR-422a竞争性结合并阻止了miR-422a对它的靶基因FOXQ1的抑制作用，最终导致NPC转移，EMT和多西他赛化学耐药。此外，circCRIM1高表达与NPC患者的不良生存有关。我们建立了基于circCRIM1表达和N期的预后模型，可有效预测NPC患者远处转移的风险和对含多西他赛的诱导化疗的治疗反应。结论我们的发现揭示了circCRIM1在通过ceRNA机制促进NPC转移和化学耐药中的关键作用，并为NPC患者的预后和治疗抵抗提供了可利用的生物标志物和治疗靶标。