The LncRNA EPEL Promotes Lung Cancer Cell Proliferation Through E2F Target Activation
The LncRNA EPEL Promotes Lung Cancer Cell Proliferation Through E2F Target Activation
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长链非编码RNA（LncRNA）EPEL通过激活E2F靶基因促进肺癌细胞增殖
DOI：
10.1159/000487460
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Kim, Youn-Jae
中科院分区：
文献类型：
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作者：
Park, Seong-Min;Choi, Eun-Young;Kim, Youn-Jae
背景/目的：最近的研究表明，许多长的非编码RNA(LncRNAs)在多种癌症中发挥致癌或肿瘤抑制作用。肺癌是全球癌症相关死亡的主要原因，许多肺癌患者手术后经常复发，即使是早期患者也是如此。然而，lncRNAs在肺癌中的致癌或抑瘤作用及其临床意义尚未完全阐明。方法：利用带有临床信息的公共微阵列数据，研究E2F介导的细胞增殖促进型LncRNA(EPEL)表达与肺癌患者生存率之间的关系。通过EPEL的siRNA敲除来分析两个肺癌细胞系中与癌症相关的表型。对基因表达数据进行基因集分析，以确定受EPEL调控的途径。采用RNA免疫沉淀法、RT-qPCR和芯片分析等方法研究EPEL调控靶基因的功能。结果：EPEL被称为LOC90768和MGC45800，与肺癌患者的复发和生存相关，并通过激活E2F靶基因促进肺癌细胞的增殖。Epel基因敲除可特异性下调肺癌细胞中细胞周期相关E2F靶基因的表达，包括细胞周期蛋白B1(CCNB1)，但不能下调与细胞凋亡或代谢相关的E2F靶基因的表达。EPEL与E2F1相互作用，通过改变E2F1与E2F靶启动子的结合效率来调控E2F靶基因的表达。此外，EPEL和CCNB1的单独和联合表达水平是肺癌的可靠预后标记物。结论：考虑到EPEL对细胞周期相关的E2F靶基因的特异性影响及其与肺癌患者预后的显著相关性，我们认为通过E2F靶基因对EPEL的转录调控可能是开发肺癌新的治疗策略的一个靶点。(C)2018年作者(S)由S.Karger AG，巴塞尔出版
Background/Aims: Recent studies have revealed that many long non-coding RNAs (lncRNAs) play oncogenic or tumor-suppressive roles in various cancers. Lung cancer is the leading cause of cancer-related death worldwide, and many lung cancer patients frequently relapse after surgery, even those in the early stages. However, the oncogenic or tumor-suppressive roles and clinical implications of lncRNAs in lung cancer have not been fully elucidated. Methods: The association between an E2F-mediated cell proliferation enhancing lncRNA (EPEL) expression and lung cancer patient survival was accessed using public microarray data with clinical information. Cancer-related phenotypes were analyzed by the siRNA knockdown of EPEL in two lung cancer cell lines. Gene set analysis of gene expression data were performed to identify pathways regulated by EPEL. RNA immunoprecipitation, RT-qPCR, and ChIP assays were performed to explore the functions of selected target genes regulated by EPEL. Results: EPEL, known as LOC90768 and MGC45800, was associated with the relapse and survival of lung cancer patients and promoted lung cancer cell proliferation through the activation of E2F target genes. EPEL knockdown specifically down-regulated the expression of cell cycle-related E2F target genes, including Cyclin B1 (CCNB1), in lung cancer cells but not that of apoptosis-or metabolism-related E2F target genes. EPEL interacted with E2F1 and regulated the expression of the E2F target genes by changing the binding efficiency of E2F1 to the E2F target promoters. Moreover, the expression levels of EPEL and CCNB1 both alone and in combination were robust prognostic markers for lung cancer. Conclusions: Considering its specific effects on cell cycle-related E2F target genes and its significant association with the prognosis of lung cancer patients, we suggest that the transcriptional regulation of EPEL through E2F target genes is potentially a target for the development of novel therapeutic strategies for lung cancer patients. (C) 2018 The Author(s) Published by S. Karger AG, Basel