长链非编码 RNA lncTCF7 通过激活 Wnt 信号促进人肝癌干细胞自我更新。

The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling.

机构信息

CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

Department of Hepatobiliary Surgery, PLA General Hospital, Beijing 100853, China.

出版信息

Cell Stem Cell. 2015 Apr 2;16(4):413-25. doi: 10.1016/j.stem.2015.03.003.

DOI:10.1016/j.stem.2015.03.003

PMID:25842979

Abstract

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.

摘要

肝细胞癌（HCC）是最常见的肝癌亚型，其特点是复发率高和异质性。肝癌干细胞（CSCs）可能对这两种病理特性都有贡献，但它们自我更新和维持的机制还知之甚少。在这里，我们使用转录组微阵列分析，鉴定出一种在 HCC 肿瘤和肝 CSCs 中高度表达的长链非编码 RNA（lncRNA），称为 lncTCF7。lncTCF7 是肝 CSC 自我更新和肿瘤增殖所必需的。从机制上讲，lncTCF7 将 SWI/SNF 复合物募集到 TCF7 的启动子上，以调节其表达，从而激活 Wnt 信号通路。我们的数据表明，lncTCF7 介导的 Wnt 信号通路促使肝 CSC 的自我更新和肿瘤增殖。因此，综上所述，我们已经确定了一个基于 lncRNA 的 Wnt 信号调节回路，该回路促进了肝癌干细胞的致瘤活性，突出了 lncRNA 在肿瘤生长和增殖中的作用。