ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway. (1st March 2020)

• Record Type: Journal Article
• Authors: Wang, Nuozhou; Li, Ming-yue; Liu, Yi; Yu, Jianqing; Ren, Jianwei; Zheng, Zhiyuan; Wang, Shanshan; Yang, Shucai; Yang, Sheng-li; Liu, Li-ping; Hu, Bao-guang; Chong, Charing CN.; Merchant, Juanita L.; Lai, Paul BS.; Chen, George Gong
• Is Part Of: Cancer letters. Volume 472(2020)
• Page Start: 70
• Page End: 80
• Publication Date: 2020-03-01
• Subjects: Hepatocellular carcinoma -- Liver cancer stemness -- Recurrence -- Notch1 -- ZBP-89; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.12.026
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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 stemness 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 stemness via inhibiting the Notch1 signaling. Highlights: ZBP-89 is negatively correlated with HCC recurrence. ZBP-89 down-regulates the self-renewal of liver CSCs by suppressing Notch1. ZBP-89 impedes the formation of NICD1-MAML1 complex. ZBP-89 acts as a transcription repressor to inactive NICD1 target genes.