A long noncoding RNA perturbs the circadian rhythm of hepatoma cells to facilitate hepatocarcinogenesis.
A long noncoding RNA perturbs the circadian rhythm of hepatoma cells to facilitate hepatocarcinogenesis.
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长非编码RNA扰乱肝癌细胞的昼夜节律，促进肝癌发生
DOI：
10.1016/j.neo.2014.11.004
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发表时间：
2015-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Xiaodong
中科院分区：
文献类型：
--
作者：
Cui, Ming;Zheng, Minying;Sun, Baodi;Wang, Yue;Ye, Lihong;Zhang, Xiaodong
生物钟昼夜节律调节因子（Clock circadian regulator，CLOCK）/脑和肌肉类淀粉样蛋白-1（brain and muscle arnt-like protein-1，BMAL 1）复合体通过触发基因表达的周期性改变来调控昼夜节律。然而，肝细胞癌（HCC）生物钟紊乱的潜在机制仍不清楚。在这里，我们报告了一个长的非编码RNA（lncRNA），在肝癌（HULC）中高度上调，有助于肝癌细胞昼夜节律的扰动。我们的观察表明，HULC能够提高肝癌细胞中CLOCK及其下游昼夜节律振荡器，如周期昼夜节律钟1和隐花色素昼夜节律钟1的表达水平。引人注目的是，HULC改变了肝癌细胞中CLOCK的表达模式，延长了CLOCK的周期性表达。从机制上讲，HULC和CLOCK mRNA 5'非翻译区之间的互补碱基配对破坏了HULC调节的CLOCK表达，互补区中的突变体未能实现该事件。免疫组化染色和实时定量聚合酶链反应证实，CLOCK在HCC组织中的表达水平升高，HULC和CLOCK在临床HCC组织中的表达水平呈正相关。在功能实验中，我们的数据显示，CLOCK在体外和体内参与了HULC加速肝癌细胞增殖。总之，我们的数据表明，lncRNA，HULC，是负责通过上调肝癌细胞中的昼夜节律振荡器时钟的昼夜节律的扰动，导致促进肝癌的发生。因此，我们的发现为lncRNA通过干扰HCC的昼夜节律加速肝癌发生的机制提供了新的见解。
Clock circadian regulator (CLOCK)/brain and muscle arnt-like protein-1 (BMAL1) complex governs the regulation of circadian rhythm through triggering periodic alterations of gene expression. However, the underlying mechanism of circadian clock disruption in hepatocellular carcinoma (HCC) remains unclear. Here, we report that a long noncoding RNA (lncRNA), highly upregulated in liver cancer (HULC), contributes to the perturbations in circadian rhythm of hepatoma cells. Our observations showed that HULC was able to heighten the expression levels of CLOCK and its downstream circadian oscillators, such as period circadian clock 1 and cryptochrome circadian clock 1, in hepatoma cells. Strikingly, HULC altered the expression pattern and prolonged the periodic expression of CLOCK in hepatoma cells. Mechanistically, the complementary base pairing between HULC and the 5' untranslated region of CLOCK mRNA underlay the HULC-modulated expression of CLOCK, and the mutants in the complementary region failed to achieve the event. Moreover, immunohistochemistry staining and quantitative real-time polymerase chain reaction validated that the levels of CLOCK were elevated in HCC tissues, and the expression levels of HULC were positively associated with those of CLOCK in clinical HCC samples. In functional experiments, our data exhibited that CLOCK was implicated in the HULC-accelerated proliferation of hepatoma cells in vitro and in vivo. Taken together, our data show that an lncRNA, HULC, is responsible for the perturbations in circadian rhythm through upregulating circadian oscillator CLOCK in hepatoma cells, resulting in the promotion of hepatocarcinogenesis. Thus, our finding provides new insights into the mechanism by which lncRNA accelerates hepatocarcinogenesis through disturbing circadian rhythm of HCC.
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