Long non-coding RNA HNF1A-AS1 regulates proliferation and migration in oesophageal adenocarcinoma cells.
Long non-coding RNA HNF1A-AS1 regulates proliferation and migration in oesophageal adenocarcinoma cells.
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DOI：
10.1136/gutjnl-2013-305266
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发表时间：
2014-06
期刊：
影响因子：
24.5
通讯作者：
Mori Y
中科院分区：
文献类型：
--
作者：
Yang X;Song JH;Cheng Y;Wu W;Bhagat T;Yu Y;Abraham JM;Ibrahim S;Ravich W;Roland BC;Khashab M;Singh VK;Shin EJ;Yang X;Verma AK;Meltzer SJ;Mori Y
长期的非编码RNA（增量）已显示在癌症的发展和发展中起重要作用。然而，功能性增量及其下游机制在食管腺癌（EAC）及其进展的分子发病机理中在很大程度上尚不清楚。
通过RNA测序分析鉴定出在EAC中异常上调的增量，然后使用来自25名EAC患者的组织进行定量RT-PCR（QRTPCR）验证。为了探测这些增量的功能相关性，进行了细胞生物测定与小干扰RNA介导的敲低的结合。
我们发现，相对于其相应的正常食管组织，在人的原发性EAC中，递增的HNF1A-AS1显着上调（平均折叠变化10.6，p <0.01）。我们进一步发现，HNF1A-AS1敲低可显着抑制细胞的增殖和锚固非依赖性生长，抑制S期进入，并抑制多种体外EAC模型中的细胞迁移和侵袭（P <0.05）。基因本体论分析表明，HNF1A-AS1敲低优先影响与染色质和核小体组装有关的基因，这是细胞循环进程必不可少的机制。众所周知的与癌症相关的增量H19是HNF1A-AS1敲低抑制最明显的基因。与这一发现一致，在原代EAC中，HNF1A-AS1和H19表达之间存在显着的正相关（P <0.01）。
我们在人类EAC中发现了hnf1a-as1的hnf1a-as1的异常上调。我们的发现表明，HNF1A-AS1的失调参与食管肿瘤发生，并且这种参与可能至少部分通过调节染色质和核小体组装以及H19诱导来介导。
Long non-coding RNAs (IncRNA) have been shown to play important roles in the development and progression of cancer. However, functional IncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of oesophageal adenocarcinoma (EAC) and its progression. IncRNAs that are abnormally upregulated in EACs were identified by RNA-sequencing analysis, followed by quantitative RT-PCR (qRTPCR) validation using tissues from 25 EAC patients. Cell biological assays in combination with small interfering RNA-mediated knockdown were performed in order to probe the functional relevance of these IncRNAs. We discovered that a IncRNA, HNF1A-AS1, is markedly upregulated in human primary EACs relative to their corresponding normal oesophageal tissues (mean fold change 10.6, p<0.01). We further discovered that HNF1A-AS1 knockdown significantly inhibited cell proliferation and anchorage-independent growth, suppressed S-phase entry, and inhibited cell migration and invasion in multiple in vitro EAC models (p<0.05). A gene ontological analysis revealed that HNF1A-AS1 knockdown preferentially affected genes that are linked to assembly of chromatin and the nucleosome, a mechanism essential to cell cycle progression. The well known cancer-related IncRNA, H19, was the gene most markedly inhibited by HNF1A-AS1 knockdown. Consistent to this finding, there was a significant positive correlation between HNF1A-AS1 and H19 expression in primary EACs (p<0.01). We have discovered abnormal upregulation of a IncRNA, HNF1A-AS1, in human EAC. Our findings suggest that dysregulation of HNF1A-AS1 participates in oesophageal tumorigenesis, and that this participation may be mediated, at least in part, by modulation of chromatin and nucleosome assembly as well as by H19 induction.