Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer.
Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer.
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长非编码 RNA HOTAIR 是一种 c-Myc 激活的恶性肿瘤驱动因素，对胆囊癌中的 miRNA-130a 负调节
DOI：
10.1186/1476-4598-13-156
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发表时间：
2014-06-23
期刊：
影响因子：
37.3
通讯作者：
Quan ZW
中科院分区：
文献类型：
--
作者：
Ma MZ;Li CX;Zhang Y;Weng MZ;Zhang MD;Qin YY;Gong W;Quan ZW
背景蛋白质编码基因仅占人类基因组的2%左右，而绝大多数转录本是非编码RNA，包括长链非编码RNA。越来越多的文献提出lncRNA是癌症的重要参与者。HOTAIR以前被证明是一种致癌基因和多种癌症的负预后因子。然而，其上调和HOTAIR和miRNA.MethodsA计算屏幕的HOTAIR启动子之间的相互作用的因素，有助于在很大程度上是未知的转录因子结合位点进行搜索。HOTAIR启动子活性通过荧光素酶报告基因测定来检查。HOTAIR启动子区中的c-Myc结合位点的功能通过在推定的E-box中具有核苷酸取代的启动子测定进行测试。染色质免疫沉淀和电泳迁移率改变实验证实了c-Myc与HOTAIR启动子的结合。利用在线软件程序用HOTAIR进行具有互补碱基配对的miRNAs的搜索。采用功能获得和丧失方法研究HOTAIR或miRNA-130 a的表达变化。检测65例配对胆囊癌组织中HOTAIR、c-Myc和miRNA-130 a的表达水平。HOTAIR和miRNA-130 a对胆囊癌细胞侵袭和增殖的影响进行了测试usingin vitrocell invasion和flow cytometric assays.ResultsWe证明HOTAIR是一个直接的目标，c-Myc通过相互作用与推定的c-Myc靶向反应元件（RE）在胆囊癌细胞HOTAIR的上游区域。胆囊癌组织中c-Myc与HOTAIR mRNA表达呈正相关。我们预测HOTAIR具有一个miRNA-130 a结合位点。我们的数据表明，该结合位点对于HOTAIR调控miRNA-130 a至关重要。在胆囊癌组织中HOTAIR与miRNA-130 a呈负相关。结论HOTAIR是c-Myc激活的恶性肿瘤驱动因子，其作用机制可能与抑制miRNA-130 a有关。
BackgroundProtein coding genes account for only about 2% of the human genome, whereas the vast majority of transcripts are non-coding RNAs including long non-coding RNAs. A growing volume of literature has proposed that lncRNAs are important players in cancer. HOTAIR was previously shown to be an oncogene and negative prognostic factor in a variety of cancers. However, the factors that contribute to its upregulation and the interaction between HOTAIR and miRNAs are largely unknown.MethodsA computational screen of HOTAIR promoter was conducted to search for transcription-factor-binding sites. HOTAIR promoter activities were examined by luciferase reporter assay. The function of the c-Myc binding site in the HOTAIR promoter region was tested by a promoter assay with nucleotide substitutions in the putative E-box. The association of c-Myc with the HOTAIR promoterin vivowas confirmed by chromatin immunoprecipitation assay and Electrophoretic mobility shift assay. A search for miRNAs with complementary base paring with HOTAIR was performed utilizing online software program. Gain and loss of function approaches were employed to investigate the expression changes of HOTAIR or miRNA-130a. The expression levels of HOTAIR, c-Myc and miRNA-130a were examined in 65 matched pairs of gallbladder cancer tissues. The effects of HOTAIR and miRNA-130a on gallbladder cancer cell invasion and proliferation was tested usingin vitrocell invasion and flow cytometric assays.ResultsWe demonstrate that HOTAIR is a direct target of c-Myc through interaction with putative c-Myc target response element (RE) in the upstream region of HOTAIR in gallbladder cancer cells. A positive correlation between c-Myc and HOTAIR mRNA levels was observed in gallbladder cancer tissues. We predicted that HOTAIR harbors a miRNA-130a binding site. Our data showed that this binding site is vital for the regulation of miRNA-130a by HOTAIR. Moreover, a negative correlation between HOTAIR and miRNA-130a was observed in gallbladder cancer tissues. Finally, we demonstrate that the oncogenic activity of HOTAIR is in part through its negative regulation of miRNA-130a.ConclusionTogether, these results suggest that HOTAIR is a c-Myc-activated driver of malignancy, which acts in part through repression of miRNA-130a.
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长非编码 RNA HOTAIR 是恶性肿瘤的驱动因素，可预测食管鳞状细胞癌的阴性预后并表现出致癌活性
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