Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2.
Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2.
复制标题
长链非编码RNA UPK1A-AS1表明肝细胞癌预后不良，并通过与EZH2相互作用促进细胞增殖
DOI：
10.1186/s13046-020-01748-y
复制
发表时间：
2020-10-29
期刊：
影响因子：
--
通讯作者：
Wu DH
中科院分区：
文献类型：
--
作者：
Zhang DY;Sun QC;Zou XJ;Song Y;Li WW;Guo ZQ;Liu SS;Liu L;Wu DH
长链非编码rna （lncRNAs）的失调与癌症的发生和发展有关，lncRNAs不仅是生物标志物，而且是癌症治疗的有希望的治疗靶点。越来越多的lncrna在肝细胞癌（HCC）中被报道，但它们的功能和机制尚不清楚。利用基因集富集分析研究UPK1A反义RNA 1 （UPK1A- as1）的分子机制。通过细胞计数试剂盒-8、EdU、流式细胞术、western blotting和异种移植物实验证实UPK1A-AS1在体外和体内肝癌细胞增殖中的作用。采用生物信息学分析和定量聚合酶链反应（qRT-PCR）技术探讨UPK1A-AS1与zeste同源物2增强子（EZH2）之间的相互作用。通过RNA免疫沉淀（RIP）、RNA拉下（pull-down）、western blotting和qRT-PCR证实UPK1A-AS1与EZH2之间的相互作用。UPK1A-AS1与miR-138-5p之间的相互作用通过荧光素酶报告基因和RIP检测进行检测。最后，利用the Cancer Genome Atlas数据集的RNA测序数据分析UPK1A-AS1在HCC中的表达水平和预后价值。我们发现UPK1A-AS1是一种新发现的lncRNA，通过加速细胞周期进程促进细胞增殖和肿瘤生长。细胞周期相关基因，包括CCND1、CDK2、CDK4、CCNB1和CCNB2，在过表达UPK1A-AS1的HCC细胞中显著上调。此外，过表达UPK1A-AS1可以保护HCC细胞免受顺铂毒性。在机制上，UPK1A-AS1与EZH2相互作用介导其核易位并加强其与SUZ12的结合，导致H27K3三甲基化增加。用特异性小干扰RNA靶向EZH2可破坏upk1a - as1介导的增殖和细胞周期进展相关基因的上调。此外，miR-138-5p被确定为UPK1A-AS1的直接靶点。此外，UPK1A-AS1在HCC中显著上调，UPK1A-AS1上调预示HCC患者预后不良。我们的研究表明，UPK1A-AS1通过与EZH2的相互作用和miR-138-5p的海绵作用加速细胞周期进程，从而促进HCC的发展，这表明UPK1A-AS1具有作为HCC预后和治疗的新型生物标志物的巨大潜力。在线版本包含补充材料，可在10.1186/s13046-020-01748-y获得。
Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear. Gene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo. Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets. We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Our study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy. The online version contains supplementary material available at 10.1186/s13046-020-01748-y.
登录
查看更多内容
影响因子：
37.3
作者：
Huang MD;Chen WM;Qi FZ;Sun M;Xu TP;Ma P;Shu YQ
通讯作者：
Shu YQ
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
16
作者：
Lee, Shuet Theng;Li, Zhimei;Yu, Qiang
通讯作者：
Yu, Qiang
影响因子：
16.1
作者：
Khorkova O;Hsiao J;Wahlestedt C
通讯作者：
Wahlestedt C
DOI：
10.1007/978-3-319-42059-2_1
发表时间：
2016-01-01
期刊：
NON-CODING RNAS IN COLORECTAL CANCER
影响因子：
--
作者：
Hombach, Sonja;Kretz, Markus
通讯作者：
Kretz, Markus