- 积分
- 139
- 威望
- 139
- 包包
- 450
|
2015年4月2日,中科院生物物理所范祖森课题组和陈润生院士课题组在国际权威期刊Cell Stem Cell杂志发表了题为“The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling”的研究论文。文章报告了关于长链非编码RNA lncTCF7调控人肝癌干细胞自我更新的作用及其分子机制的新发现。
/ o9 {5 [8 j$ }* P$ {$ R2 g$ Y& @2 @6 l0 y, X* r9 v/ P( p: Q' C
研究人员通过转录组芯片鉴定了人肝癌干细胞和非干细胞中差异表达的长链非编码RNA,其中lncTCF7在人肝癌干细胞和肝癌组织中显著高表达,并且定位在细胞核中。沉默lncTCF7表达,显著下调肝癌细胞重要干性转录因子的表达和体外干细胞小球的形成能力,且在动物体内显着抑制肝癌的形成和生长。lncTCF7高表达,显著促进了肝癌干细胞的自我更新能力。进一步研究发现,lncTCF7主要通过调控TCF7而活化Wnt信号通路,从而激发肝癌干细胞的自我更新作用。lncTCF7通过招募染色质重塑复合物SWI/SNF,结合到TCF7基因的启动子区,启动TCF7基因的转录。沉默SWI/SNF组分的表达则显著抑制了TCF7的转录,从而阻止了Wnt信号的活化。综上所述,lncTCF7通过招募SWI/SNF复合物,激活Wnt信号通路,在肝癌干细胞自我更新的维持中发挥重要作用。我们的研究提示,lncRNA也可以作为肝癌发生发展的重要分子,可能将成为肿瘤临床干预的重要新靶点。5 y) ]+ @8 {* i; ]3 n
5 g3 m. X Y" E2 c/ V原发性肝癌是世界五大常见癌症之一,肝癌发病率和死亡率在我国位居世界前列。因此,攻克肝癌成为当前的国家需求,迫在眉睫。肝细胞癌是原发性肝癌的主要病理亚型,缺乏有效治疗药物,复发率高,发病机理尚未阐明。近年来,肿瘤干细胞学说受到高度关注和认同,肿瘤干细胞具有自我更新和可塑性潜能,在启动肿瘤形成和生长中起着决定性作用,现有的治疗措施尚无法针对肿瘤干细胞发挥作用,这可能是导致肝癌复发和耐药的主要原因。长链非编码RNA(lncRNA)是一类转录长度大于200个核苷酸且不编码蛋白质的RNA分子。在肿瘤研究方面,lncRNA可通过多种途径调控染色质重构、蛋白加工修饰等,从而影响效应蛋白质的功能。然而,lncRNA对肝癌干细胞自我更新的调控作用尚未见报道。/ X% Y5 B7 y5 v4 w7 n9 b) @7 l
" C# }6 {" T5 J: cCell Stem Cell doi:10.1016/j.stem.2015.03.0032 z' ?+ G7 [- @4 }9 Z
6 }3 J7 s7 p+ ^2 E
The Long Noncoding RNA lncTCF7 Promotes Self-Renewal of Human Liver Cancer Stem Cells through Activation of Wnt Signaling
( T$ t& C0 c" f! f% b# ?% K' U* J( j; F! s4 w9 @$ V4 I
Yanying Wang, Lei He, Ying Du, Pingping Zhu, Guanling Huang, Jianjun Luo, Xinlong Yan, Buqing Ye, Chong Li, Pengyan Xia, Geng Zhang, Yong Tian4, Runsheng Chen, Zusen Fan, H/ b$ c; M) ~: y% P0 L# k& ~
N; ^/ G1 h9 T+ W3 x
Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer, and it is characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanisms underlying their self-renewal and maintenance are poorly understood. Here, using transcriptome microarray analysis, we identified a long noncoding RNA (lncRNA) termed lncTCF7 that is highly expressed in HCC tumors and liver CSCs. LncTCF7 is required for liver CSC self-renewal and tumor propagation. Mechanistically, lncTCF7 recruits the SWI/SNF complex to the promoter of TCF7 to regulate its expression, leading to activation of Wnt signaling. Our data suggest that lncTCF7-mediated Wnt signaling primes liver CSC self-renewal and tumor propagation. In sum, therefore, we have identified an lncRNA-based Wnt signaling regulatory circuit that promotes tumorigenic activity in liver cancer stem cells, highlighting the role that lncRNAs can play in tumor growth and propagation. |
附件: 你需要登录才可以下载或查看附件。没有帐号?注册
|