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ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway.
Cancer Letters ( IF 9.1 ) Pub Date : 2019-12-23 , DOI: 10.1016/j.canlet.2019.12.026
Nuozhou Wang 1 , Ming-Yue Li 2 , Yi Liu 3 , Jianqing Yu 1 , Jianwei Ren 1 , Zhiyuan Zheng 1 , Shanshan Wang 4 , Shucai Yang 5 , Sheng-Li Yang 6 , Li-Ping Liu 7 , Bao-Guang Hu 8 , Charing Cn Chong 1 , Juanita L Merchant 9 , Paul Bs Lai 1 , George Gong Chen 10
Affiliation  

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.

中文翻译:

ZBP-89通过抑制Notch1信号通路负调控肝癌干细胞的自我更新。

肝癌干细胞(LCSC)引发肝细胞癌(HCC),并有助于其复发和治疗耐药性。研究表明ZBP-89可作为肝癌的候选肿瘤抑制剂。我们探讨了ZBP-89在调控LCSC中的作用。这项研究是在104位HCC患者,2种细胞系和小鼠肿瘤模型的肝组织样本中进行的。我们证明了ZBP-89在LCSC中微弱表达。LCSC标志物高表达的患者在根治性手术后表现出降低的生存率和更高的复发率。ZBP-89的表达可预测复发率的降低。在肝癌组织和富集的肝肿瘤领域,LCSC标记与ZBP-89呈负相关。ZBP-89的外源表达减弱了LCSCs在体外的肿瘤球形成和继发菌落形成能力以及体内的致瘤性。此外,ZBP-89对癌症干的负面影响是Notch1依赖性的。ZBP-89通过在细胞核中定位Notch1细胞内结构域(NICD1),通过与MAML1与NICD1竞争性结合来抑制Notch1信号通路。ZBP-89通过抑制Notch1信号传导共同调节HCC干细胞。
更新日期:2019-12-23
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