ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells

被引:142
作者
Zhu, Pingping [1 ]
Wang, Yanying [1 ]
He, Lei [2 ]
Huang, Guanling [1 ,3 ]
Du, Ying [1 ]
Zhang, Geng [1 ]
Yan, Xinlong [1 ]
Xia, Pengyan [1 ]
Ye, Buqing [1 ]
Wang, Shuo [1 ]
Hao, Lu [1 ,3 ]
Wu, Jiayi [1 ,3 ]
Fan, Zusen [1 ,3 ]
机构
[1] Chinese Acad Sci, Inst Biophys, CAS, Key Lab Infect & Immun, Beijing 100101, Peoples R China
[2] Peoples Liberat Army Gen Hosp, Dept Hepatobiliary Surg, Beijing, Peoples R China
[3] Univ Chinese Acad Sci, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
EXPRESSION; ZIC2; IDENTIFICATION; FINGER; DIFFERENTIATION; PLURIPOTENCY; PROGRESSION; DYSPLASIA; WINGLESS; BIOLOGY;
D O I
10.1172/JCI81979
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Liver cancer stem cells (CSCs) have been identified and shown to have self-renewal and differentiation properties; however, the biology of these hepatic CSCs remains largely unknown. Here, we analyzed transcriptome gene expression profiles of liver CSCs and non-CSCs from hepatocellular carcinoma (HCC) cells lines and found that the transcription factor (TF) ZIC2 is highly expressed in liver CSCs. ZIC2 was required for the self-renewal maintenance of liver CSCs, as ZIC2 depletion reduced sphere formation and xenograft tumor growth in mice. We determined that ZIC2 acts upstream of the TF OCT4 and that ZIC2 recruits the nuclear remodeling factor (NURF) complex to the OCT4 promoter, thereby initiating OCT4 activation. In HCC patients, expression levels of the NURF complex were consistent with clinical severity and prognosis. Moreover, ZIC2 and OCT4 levels positively correlated to the clinicopathological stages of HCC patients. Altogether, our results indicate that levels of ZIC2, OCT4, and the NURF complex can be detected and used for diagnosis and prognosis prediction of HCC patients. Moreover, these factors may be potential therapeutic targets for eradicating liver CSCs.
引用
收藏
页码:3795 / 3808
页数:14
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