Journal
CANCER LETTERS
Volume 472, Issue -, Pages 70-80Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.12.026
Keywords
Hepatocellular carcinoma; Liver cancer sternness; Recurrence; Notch1; ZBP-89
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Funding
- Research Grants Council of the Hong Kong Special Administrative Region [14109516]
- National Natural Science Foundation of China [81472339]
- Guangdong GDNSF foundation [2018A0303130313]
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Liver cancer stem cells (LCSCs) initiate hepatocellular carcinoma (HCC) and contribute to its recurrence and treatment resistance. Studies have suggested ZBP-89 as a candidate tumor suppressor in HCC. We explored the role of ZBP-89 in the regulation of LCSCs. This study was performed in liver tissue samples from 104 HCC patients, 2 cell lines and mouse tumor models. We demonstrated that ZBP-89 was weakly expressed in LCSCs. Patients with high expression of LCSC markers displayed reduced survivals and higher recurrence rates after curative surgical operation. The expression of ZBP-89 was predictive for decreased recurrence. LCSC markers were negatively correlated with ZBP-89 in HCC tissues and in enriched liver tumor spheres. The exogenous expression of ZBP-89 attenuated the tumor-sphere formation and secondary colony formation capabilities of LCSCs in vitro and tumorigenicity in vivo. Furthermore, the negative effect of ZBP-89 on cancer sternness was Notch1-dependent. Localized with Notch1 intracellular domain (NICD1) in the nucleus, ZBP-89 repressed the Notch1 signaling pathway by competitive binding to NICD1 with MAML1. Collectively, ZBP-89 negatively regulates HCC sternness via inhibiting the Notch1 signaling.
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