Subjects: Biology >> Biophysics submitted time 2016-05-11
Zhu, Pingping
Wang, Yanying
Huang, Guanling
Du, Ying
Zhang, Geng
Yan, Xinlong
Xia, Pengyan
Ye, Buqing
Wang, Shuo
Hao, Lu
Wu, Jiayi
Fan, Zusen
He, Lei
Huang, Guanling
Hao, Lu
Wu, Jiayi
Fan, Zusen
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.
Peer Review Status:
Awaiting Review
Subjects: Biology >> Biophysics submitted time 2016-05-11
Zhu, Pingping
Zhu, Pingping
Wang, Yanying
Du, Ying
Huang, Guanling
Zhang, Geng
Yan, Xinlong
Fan, Zusen
He, Lei
Abstract： Liver cancer stem cells (CSCs) harbour self-renewal and differentiation properties, accounting for chemotherapy resistance and recurrence. However, the molecular mechanisms to sustain liver CSCs remain largely unknown. In this study, based on analysis of several hepatocellular carcinoma (HCC) transcriptome datasets and our experimental data, we find that C8orf4 is weakly expressed in HCC tumours and liver CSCs. C8orf4 attenuates the self-renewal capacity of liver CSCs and tumour propagation. We show that NOTCH2 is activated in liver CSCs. C8orf4 is located in the cytoplasm of HCC tumour cells and associates with the NOTCH2 intracellular domain, which impedes the nuclear translocation of N2ICD. C8orf4 deletion causes the nuclear translocation of N2ICD that triggers the NOTCH2 signalling, which sustains the stemness of liver CSCs. Finally, NOTCH2 activation levels are consistent with clinical severity and prognosis of HCC patients. Altogether, C8orf4 negatively regulates the self-renewal of liver CSCs via suppression of NOTCH2 signalling.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biophysics submitted time 2016-05-11
Wang, Yanying
Du, Ying
Zhu, Pingping
Huang, Guanling
Yan, Xinlong
Ye, Buqing
Li, Chong
Xia, Pengyan
Zhang, Geng
Fan, Zusen
He, Lei
Huang, Guanling
Fan, Zusen
Luo, Jianjun
Tian, Yong
Chen, Runsheng
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 (IncRNA) termed IncTCF7 that is highly expressed in HCC tumors and liver CSCs. LncTCF7 is required for liver CSC self-renewal and tumor propagation. Mechanistically, IncTCF7 recruits the SWI/SNF complex to the promoter of TCF7 to regulate its expression, leading to activation of Wnt signaling. Our data suggest that IncTCF7-mediated Wnt signaling primes liver CSC self-renewal and tumor propagation. In sum, therefore, we have identified an IncRNA-based Wnt signaling regulatory circuit that promotes tumorigenic activity in liver cancer stem cells, highlighting the role that IncRNAs can play in tumor growth and propagation.
Peer Review Status:Awaiting Review
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