Long noncoding RNAs associated with liver regeneration 1 accelerates hepatocyte proliferation during liver regeneration by activating Wnt/-Catenin signaling
Long noncoding RNAs associated with liver regeneration 1 accelerates hepatocyte proliferation during liver regeneration by activating Wnt/-Catenin signaling
复制标题
与肝再生相关的长非编码 RNA 1 通过激活 Wnt/-Catenin 信号传导加速肝再生过程中的肝细胞增殖
DOI：
10.1002/hep.26361
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发表时间：
2013-08-01
期刊：
影响因子：
13.5
通讯作者：
Sun, Shu-han
中科院分区：
文献类型：
--
作者：
Xu, Dan;Yang, Fu;Sun, Shu-han
近年来，长链非编码RNA（longnoncodingRNAs，lncRNAs）作为一类新的生物学功能调节因子被研究。最近的一项研究报道，lncRNA控制肝细胞癌（HCC）中的细胞增殖。然而，lncRNA在肝再生中的作用和总体机制在很大程度上仍然未知。为了解决这个问题，我们进行了全基因组lncRNA微阵列分析在2/3部分肝切除术（PH）后的小鼠在不同的时间点肝再生过程中。结果揭示了lncRNA亚组的差异表达，特别是在肝再生期间与Wnt/β-连环蛋白信号传导相关的特异性差异表达lncRNA（与肝再生相关的lncRNA，称为lncRNA-LALR 1）。通过在体外和体内沉默和过表达该lncRNA来评估lncRNA-LALR 1的功能。我们发现lncRNA-LALR 1通过促进细胞周期的进展来增强体外肝细胞增殖。此外，我们发现lncRNA-LALR 1在体内肝再生过程中加速小鼠肝细胞增殖和细胞周期进程。从机制上讲，我们发现lncRNA-LALR 1通过抑制Axin 1激活Wnt/β-catenin信号通路促进细胞周期蛋白D1的表达。此外，lncRNA-LALR 1主要通过将CTCF募集到AXIN 1启动子区来抑制Axin 1的表达。我们还鉴定了lncRNA-LALR 1的人类直系同源RNA（lncRNA-hLALR 1），并发现它在人类肝组织中表达。结论：lncRNA-LALR 1通过激活Wnt/β-catenin信号通路促进细胞周期进程并加速肝细胞增殖。靶向lncRNA-LALR 1的药物干预可能通过诱导肝再生在肝衰竭和肝移植中具有治疗益处。（肝病学2013;58：739-751）
In recent years, long noncoding RNAs (lncRNAs) have been investigated as a new class of regulators of biological function. A recent study reported that lncRNAs control cell proliferation in hepatocellular carcinoma (HCC). However, the role of lncRNAs in liver regeneration and the overall mechanisms remain largely unknown. To address this issue, we carried out a genome-wide lncRNA microarray analysis during liver regeneration in mice after 2/3 partial hepatectomy (PH) at various timepoints. The results revealed differential expression of a subset of lncRNAs, notably a specific differentially expressed lncRNA associated with Wnt/-catenin signaling during liver regeneration (an lncRNA associated with liver regeneration, termed lncRNA-LALR1). The functions of lncRNA-LALR1 were assessed by silencing and overexpressing this lncRNA in vitro and in vivo. We found that lncRNA-LALR1 enhanced hepatocyte proliferation by promoting progression of the cell cycle in vitro. Furthermore, we showed that lncRNA-LALR1 accelerated mouse hepatocyte proliferation and cell cycle progression during liver regeneration in vivo. Mechanistically, we discovered that lncRNA-LALR1 facilitated cyclin D1 expression through activation of Wnt/-catenin signaling by way of suppression of Axin1. In addition, lncRNA-LALR1 inhibited the expression of Axin1 mainly by recruiting CTCF to the AXIN1 promoter region. We also identified a human ortholog RNA of lncRNA-LALR1 (lncRNA-hLALR1) and found that it was expressed in human liver tissues. Conclusion: lncRNA-LALR1 promotes cell cycle progression and accelerates hepatocyte proliferation during liver regeneration by activating Wnt/-catenin signaling. Pharmacological intervention targeting lncRNA-LALR1 may be therapeutically beneficial in liver failure and liver transplantation by inducing liver regeneration. (Hepatology 2013;58:739-751)