Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression.
Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression.
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DOI：
10.1186/s12943-017-0674-z
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发表时间：
2017-06-14
期刊：
影响因子：
37.3
通讯作者：
Wang YC
中科院分区：
文献类型：
--
作者：
Jen J;Tang YA;Lu YH;Lin CC;Lai WW;Wang YC
Oct 4是一个关键的干性转录因子，在肺癌中过表达。在这里，我们揭示了Oct 4对长非编码RNA（lncRNA）的一种新的转录调控。lncRNA已成为癌症进展中的重要参与者。Oct 4染色质免疫沉淀（ChIP）测序和几个lncRNA数据库与文献注释整合，以确定Oct 4调节的lncRNA。进行荧光素酶活性、qRT-PCR和ChIP-PCR测定以检查10月4日的lncRNA转录调节。在细胞增殖、迁移和侵袭测定中进行Oct 4和下游lncRNA的重构实验，以证实Oct 4-lncRNA信号传导轴促进肺癌细胞生长和运动。采用qRT-PCR分析124例肺癌患者中Oct 4和lncRNA的表达相关性。使用多变量考克斯回归和Kaplan-Meier分析进一步评估Oct 4/lncRNA信号传导轴的临床意义。我们证实了7种lncRNA通过直接结合Oct 4而上调。其中，核旁斑装配转录本1（NEAT 1）、转移相关肺腺癌转录本1（MALAT 1）和尿路上皮癌相关转录本1（UCA 1）通过启动子或增强子激活被验证为Oct 4转录靶点。我们发现过表达NEAT 1或MALAT 1的肺癌细胞和用NEAT 1或MALAT 1重建的Oct 4沉默细胞促进细胞增殖、迁移和侵袭。此外，NEAT 1或MALAT 1的敲低消除了Oct 4介导的肺癌细胞生长和运动。这些基于细胞的结果表明Oct 4/NEAT 1或Oct 4/MALAT 1轴促进肿瘤发生。临床上，Oct 4/NEAT 1/MALAT 1共过表达是124例肺癌患者预后不良的独立预测因素。我们的研究揭示了Oct 4通过启动子和增强子结合转录激活NEAT 1和MALAT 1以促进细胞增殖和运动的新机制，并导致肺肿瘤发生和预后不良。本文的在线版本（doi：10.1186/s12943-017-0674-z）包含补充材料，可供授权用户使用。
Oct4, a key stemness transcription factor, is overexpressed in lung cancer. Here, we reveal a novel transcription regulation of long non-coding RNAs (lncRNAs) by Oct4. LncRNAs have emerged as important players in cancer progression. Oct4 chromatin-immunoprecipitation (ChIP)-sequencing and several lncRNA databases with literature annotation were integrated to identify Oct4-regulated lncRNAs. Luciferase activity, qRT-PCR and ChIP-PCR assays were conducted to examine transcription regulation of lncRNAs by Oct4. Reconstitution experiments of Oct4 and downstream lncRNAs in cell proliferation, migration and invasion assays were performed to confirm the Oct4-lncRNAs signaling axes in promoting lung cancer cell growth and motility. The expression correlations between Oct4 and lncRNAs were investigated in 124 lung cancer patients using qRT-PCR analysis. The clinical significance of Oct4/lncRNAs signaling axes were further evaluated using multivariate Cox regression and Kaplan-Meier analyses. We confirmed that seven lncRNAs were upregulated by direct binding of Oct4. Among them, nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and urothelial carcinoma-associated 1 (UCA1) were validated as Oct4 transcriptional targets through promoter or enhancer activation. We showed that lung cancer cells overexpressing NEAT1 or MALAT1 and the Oct4-silenced cells reconstituted with NEAT1 or MALAT1 promoted cell proliferation, migration and invasion. In addition, knockdown of NEAT1 or MALAT1 abolished Oct4-mediated lung cancer cell growth and motility. These cell-based results suggested that Oct4/NEAT1 or Oct4/MALAT1 axis promoted oncogenesis. Clinically, Oct4/NEAT1/MALAT1 co-overexpression was an independent factor for prediction of poor outcome in 124 lung cancer patients. Our study reveals a novel mechanism by which Oct4 transcriptionally activates NEAT1 via promoter and MALAT1 via enhancer binding to promote cell proliferation and motility, and led to lung tumorigenesis and poor prognosis. The online version of this article (doi:10.1186/s12943-017-0674-z) contains supplementary material, which is available to authorized users.