Circular RNA CRIM1 functions as a ceRNA to promote nasopharyngeal carcinoma metastasis and docetaxel chemoresistance through upregulating FOXQ1
Circular RNA CRIM1 functions as a ceRNA to promote nasopharyngeal carcinoma metastasis and docetaxel chemoresistance through upregulating FOXQ1
复制标题
环状RNA CRIM1作为ceRNA通过上调FOXQ1促进鼻咽癌转移和多西紫杉醇化疗耐药。
DOI：
10.1186/s12943-020-01149-x
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发表时间：
2020-02-15
期刊：
影响因子：
37.3
通讯作者：
Li, Yingqin
中科院分区：
文献类型：
--
作者：
Hong, Xiaohong;Liu, Na;Li, Yingqin
研究背景环状RNA（Circular RNA，circRNA）是一种新型的非编码RNA（noncoding RNA，ncRNA），被认为是重要的基因表达调控因子，与肿瘤的发生、发展密切相关。然而，circRNA在鼻咽癌（NPC）中的作用仍然很大程度上未知。方法采用RNA测序技术，分析两种不同转移能力的鼻咽癌细胞系（S18和S26细胞）中circRNA的表达谱。采用定量逆转录PCR方法检测circCRIM 1在鼻咽癌细胞和组织中的表达水平。通过体外和体内实验研究circCRIM 1对鼻咽癌转移和EMT的影响。通过RNA免疫沉淀、荧光素酶报告基因检测、生物素标记的miRNA pull-down检测、荧光原位杂交等方法，证实了circCRIM 1与miR-422 a在鼻咽癌中的相互作用。评价circCRIM 1在鼻咽癌转移和化疗敏感性中的临床应用价值。结果我们发现circCRIM 1在高转移性NPC细胞中上调。CircCRIM 1在有远处转移的鼻咽癌组织中也过表达，其过表达促进了鼻咽癌细胞的转移和EMT。在机制上，circCRIM 1竞争性结合miR-422 a并阻止miR-422 a对其靶基因FOXQ 1的抑制作用，最终导致NPC转移、EMT和多西他赛化疗耐药。此外，circCRIM 1高表达与NPC患者的不良生存相关。我们建立了一个基于circCRIM 1表达和N分期的预后模型，有效地预测了NPC患者的远处转移风险和对含紫杉醇诱导化疗的治疗反应。结论circCRIM 1通过ceRNA机制在促进鼻咽癌转移和化疗耐药中发挥重要作用，为鼻咽癌患者的预后和治疗耐药提供了可开发的生物标志物和治疗靶点。
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.