Zic2 Drives Self-renewal of Human Liver Cancer Stem Cells
Zic2 Drives Self-renewal of Human Liver Cancer Stem Cells
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ZIC2依赖性OCT4激活驱动人肝癌干细胞的自我更新
DOI：
10.1172/jci81979
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Zusen Fan
中科院分区：
文献类型：
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作者：
Pingping Zhu;Yanying Wang;Lei He;Guanling Huang;Ying Du;Geng Zhang;Xinlong Yan;Pengyan Xia;Buqing Ye;Shuo Wang;Lu Hao;Jiayi Wu;Zusen Fan
肝癌干细胞（CSCs）已被鉴定并显示出具有自我更新和分化特性；然而，这些肝CSCs的生物学特性在很大程度上仍然未知。在此，我们分析了肝细胞癌（HCC）细胞系的肝干细胞和非肝干细胞的转录组基因表达谱，发现转录因子（TF） ZIC2在肝干细胞中高表达。ZIC2对于肝CSCs的自我更新维持是必需的，因为ZIC2的缺失减少了小鼠体内球体的形成和异种移植肿瘤的生长。我们确定ZIC2作用于TF OCT4的上游，并且ZIC2将核重塑因子（NURF）复合物招募到OCT4启动子，从而启动OCT4激活。在HCC患者中，NURF复合物的表达水平与临床严重程度和预后一致。ZIC2和OCT4水平与HCC患者的临床病理分期呈正相关。总之，我们的研究结果表明，ZIC2、OCT4和NURF复合物的水平可以检测并用于HCC患者的诊断和预后预测。此外，这些因素可能是根除肝CSCs的潜在治疗靶点。
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.