The C/D box small nucleolar RNA SNORD52 regulated by Upf1 facilitates Hepatocarcinogenesis by stabilizing CDK1
The C/D box small nucleolar RNA SNORD52 regulated by Upf1 facilitates Hepatocarcinogenesis by stabilizing CDK1
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Upf1 调控的 C/D 盒小核仁 RNA SNORD52 通过稳定 CDK1 促进肝癌发生。
DOI：
10.7150/thno.47677
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Chang, Lei
中科院分区：
文献类型：
--
作者：
Li, Cuicui;Wu, Long;Chang, Lei
基本原理：了解小核仁RNA(SnoRNAs)在肝癌发生中的作用将为确定肝细胞癌的诊断和治疗靶点提供新的途径。我们先前的研究证实了UPF1在肝细胞癌中的抑瘤作用。方法：采用RNA测序技术检测UPF1调控的snoRNAs在肝癌细胞中的表达谱，进而研究SNORD52在肝癌组织和不同细胞系中的表达及其意义。通过功能获得和功能丧失实验证实了SNORD52在体外和体内对肝癌细胞的促肿瘤作用。结果：检测到多种snoRNAs，其中人C/D盒小核仁RNA SNORD52在肝细胞癌组织中表达上调，并与UPF1表达呈负相关，SNORD52高表达患者的临床预后较差。SNORD52在体内和体外均能促进肝癌的发生。从机制上讲，KEGG分析表明SNORD52上调了肝癌细胞中一系列细胞周期基因的表达。我们进一步证实SNORD52通过增强CDK1蛋白的稳定性而上调CDK1，并且SNORD52的功能依赖于CDK1的存在。结论：SNORD52可能是一种潜在的肝细胞癌的生物标志物。靶向UPF1/SNORD52/CDK1通路可能对肝癌有治疗潜力。
Rationale: Understanding the roles of small nucleolar RNAs (snoRNAs) in hepatocarcinogenesis will provide new avenues to identify diagnostic and therapeutic targets for hepatocellular carcinoma (HCC). Our previous research confirmed the tumor-suppressive effect of Up-frameshift 1 (Upf1) in HCC. Herein, we examined the expression profiles of snoRNAs regulated by Upf1 in hepatoma cells.Methods: We examined the expression profiles of snoRNAs regulated by Upf1 in hepatoma cells using RNA-sequencing analysis and then investigated the expression and significance of SNORD52 in HCC tissue and different cell lines. The protumorigenic effects of SNORD52 on HCC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function assays. RNA pull-down assays and mass spectrometry were used to identify the RNA-binding protein that binds to SNORD52.Results: Many snoRNAs were identified; one of which, the human C/D box small nucleolar RNA SNORD52, was upregulated in HCC tissues and negatively correlated with Upf1 expression, and patients with higher SNORD52 expression had a poor clinical prognosis. SNORD52 promoted HCC tumorigenesis both in vitro and in vivo. Mechanistically, KEGG analysis showed that SNORD52 upregulated a series of cell cycle genes in HCC cells. We further confirmed that SNORD52 upregulated CDK1 by enhancing the stability of CDK1 proteins and that the function of SNORD52 depends on the presence of CDK1.Conclusion: Overall, the present study indicates that SNORD52 could be a potential biomarker for HCC. Targeting the Upf1/SNORD52/CDK1 pathway might have therapeutic potential for HCC.