LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway
LINC00673 is activated by YY1 and promotes the proliferation of breast cancer cells via the miR-515-5p/MARK4/Hippo signaling pathway
复制标题
LINC00673被YY1激活并通过miR-515-5p/MARK4/Hippo信号通路促进乳腺癌细胞增殖
DOI：
10.1186/s13046-019-1421-7
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发表时间：
2019-10-17
影响因子：
11.3
通讯作者：
Pang, Da
中科院分区：
文献类型：
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作者：
Qiao, Kun;Ning, Shipeng;Pang, Da
背景越来越多的研究表明长链非编码RNA（longnoncodingRNAs，lncRNA）在肿瘤的发生和发展中起重要作用。LncRNA通过表观遗传修饰和竞争性内源性RNA（ceRNA）机制靶向特定基因而充当肿瘤促进剂或抑制剂。本研究旨在探讨长基因间非蛋白编码RNA 673（LINC 00673）在乳腺癌发生发展中的作用及其机制。方法采用实时荧光定量PCR（qRT-PCR）检测LINC 00673在乳腺癌组织及癌旁正常组织中的表达。进行功能获得和功能丧失实验以研究LINC 00673在体外和体内的生物学功能。本研究通过RNA测序、双荧光素酶报告基因检测、染色质免疫沉淀（ChIP）检测和挽救实验，探讨LINC 00673在乳腺癌中的作用机制。LINC 00673在乳腺癌组织中表现出显著增加的表达趋势，并且与乳腺癌患者的不良预后相关。重要的是，LINC 00673耗竭通过抑制细胞周期和增加细胞凋亡来抑制乳腺癌细胞增殖。此外，靶向LINC 00673的阿索治疗在体内基本上抑制了乳腺癌细胞增殖。在机制上，发现LINC 00673通过海绵状miR-515- 5 p调节MARK 4表达而充当ceRNA，从而抑制Hippo信号传导途径。结论YY 1激活的LINC 00673可能通过吸收miR-515- 5 p上调MARK 4进而抑制Hippo信号通路而发挥致癌作用，并可能成为潜在的治疗靶点。
BackgroundAn increasing number of studies have shown that long noncoding RNAs (lncRNAs) play essential roles in tumor initiation and progression. LncRNAs act as tumor promoters or suppressors by targeting specific genes via epigenetic modifications and competing endogenous RNA (ceRNA) mechanisms. In this study, we explored the function and detailed mechanisms of long intergenic nonprotein coding RNA 673 (LINC00673) in breast cancer progression.MethodsQuantitative real-time PCR (qRT-PCR) was used to examine the expression of LINC00673 in breast cancer tissues and in adjacent normal tissues. Gain-of-function and loss-of function experiments were conducted to investigate the biological functions of LINC00673 in vitro and in vivo. We also explored the potential role of LINC00673 as a therapeutic target using antisense oligonucleotide (ASO) in vivo.RNA sequencing (RNA-seq), dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP) assay, and rescue experiments were performed to uncover the detailed mechanism of LINC00673 in promoting breast cancer progression.ResultsIn the present study, LINC00673 displayed a trend of remarkably increased expression in breast cancer tissues and was associated with poor prognosis in breast cancer patients. Importantly, LINC00673 depletion inhibited breast cancer cell proliferation by inhibiting the cell cycle and increasing apoptosis. Furthermore, ASO therapy targeting LINC00673 substantially suppressed breast cancer cell proliferation in vivo. Mechanistically, LINC00673 was found to act as a ceRNA by sponging miR-515-5p to regulate MARK4 expression, thus inhibiting the Hippo signaling pathway. Finally, ChIP assay showed that the transcription factor Yin Yang 1 (YY1) could bind to the LINC00673 promoter and increase its transcriptionin cis.ConclusionsYY1-activated LINC00673 may exert an oncogenic function by acting as a sponge for miR-515-5p to upregulate the MARK4 and then inhibit Hippo signaling pathway, and may serve as a potential therapeutic target.