ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells
Pingping Zhu, … , Jiayi Wu, Zusen Fan
Pingping Zhu, … , Jiayi Wu, Zusen Fan
Published August 31, 2015
Citation Information: J Clin Invest. 2015;125(10):3795-3808. https://doi.org/10.1172/JCI81979.
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ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cells

Abstract

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.

Authors

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

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Figure 9

NURF complex levels are consistent with HCC severity and prognosis.

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NURF complex levels are consistent with HCC severity and prognosis. (A) ...
(A) The NURF complex is highly expressed in HCC datasets provided by Wang’s cohort (GSE14520). (B and C) High expression of the NURF complex was verified in HCC samples by quantitative RT-PCR (B) and Western blot (C). eHCC, early HCC; aHCC, advanced HCC. (D) Expression of BPTF, SNF2L, and RBBP4 was observed by IHC staining (left panel). Photon intensity was calculated using Image-Pro Plus 6 (right panel). Scale bars: 50 μm. (E and F) High BPTF expression is consistent with late clinicopathological stages (E) and early recurrence (F) of HCC patients provided by Wang’s cohort (GSE14520). (G) Expression levels of the NURF complex are correlated with prognosis prediction of HCC patients. HCC samples were divided into 2 groups according to BPTF expression levels followed by Kaplan-Meier survival analysis. For A, E, and F, data are shown as box-and-whisker plots. Whiskers below and above boxes extend to the 5th and 95th percentiles, respectively. Horizontal lines within boxes represent median levels of gene intensity. Boxes represent interquartile range (IQR); upper and lower edges correspond to the 75th and 25th percentiles, respectively. For B and D, data are shown as means ± SD. Two-tailed Student’s t test was used for statistical analysis. *P < 0.05 and **P < 0.01. Experiments were repeated at least 3 times.