Down-Regulation of the Cyclin-Dependent Kinase Inhibitor p57 Is Mediated by Jab1/Csn5 in Hepatocarcinogenesis
Down-Regulation of the Cyclin-Dependent Kinase Inhibitor p57 Is Mediated by Jab1/Csn5 in Hepatocarcinogenesis
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DOI：
10.1002/hep.28372
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发表时间：
2016-03-01
期刊：
影响因子：
13.5
通讯作者：
Claret, Francois X.
中科院分区：
文献类型：
--
作者：
Guo, Hui;Jing, Li;Claret, Francois X.
细胞周期蛋白依赖性激酶抑制剂p57（KIP 2）的下调可加速肝细胞癌（HCC）的生长和侵袭，提示p57可能在肝癌的发生中起重要作用。然而，导致HCC中p57下调的机制或致癌信号仍有待确定。在此，我们证明了Jab 1/Csn 5表达与HCC组织中p57水平呈负相关。肿瘤样本的Kaplan-Meier分析显示，Jab 1/Csn 5高表达伴p57低表达与总生存率低相关。在化学诱导的大鼠肝癌模型中，在癌变过程中也观察到Jab 1和p57表达的反向模式。我们还发现，在HCC细胞中Jab 1介导的p57蛋白水解机制依赖于26 S-蛋白酶体抑制剂。我们进一步证明，Jab 1和p57之间的直接物理相互作用触发p57下调，独立于Skp 2和Akt途径，在HCC细胞中。这些数据表明，Jab 1是一个重要的上游负调控p57和Jab 1在肝癌的异常表达可能会导致p57水平显着下降，并有助于肿瘤细胞的生长。此外，Jab 1缺失诱导的p57水平的恢复抑制了肿瘤细胞的生长，并进一步增加了HCC细胞的细胞凋亡。此外，沉默Jab 1表达进一步增强了顺铂诱导的肝癌细胞凋亡的抗肿瘤作用。结论：Jab 1-p57通路是肝癌化疗耐药的重要机制，可能成为肝癌治疗的潜在靶点。
Down-regulation of p57 (KIP2) cyclin-dependent kinase inhibitors accelerates the growth and invasion of hepatocellular carcinoma (HCC), suggesting that p57 may play an important role in liver carcinogenesis. However, the mechanism or oncogenic signal leading to p57 down-regulation in HCC remains to be determined. Herein, we demonstrated that Jab1/Csn5 expression is negatively correlated with p57 levels in HCC tissues. Kaplan-Meier analysis of tumor samples revealed that high Jab1/Csn5 expression with concurrent low p57 expression is associated with poor overall survival. The inverse pattern of Jab1 and p57 expression was also observed during carcinogenesis in a chemically induced rat HCC model. We also found that mechanistically, Jab1-mediated p57 proteolysis in HCC cells is dependent on 26S-proteasome inhibitors. We further demonstrated that direct physical interaction between Jab1 and p57 triggers p57 down-regulation, independently of Skp2 and Akt pathways, in HCC cells. These data suggest that Jab1 is an important upstream negative regulator of p57 and that aberrant expression of Jab1 in HCC could lead to a significant decrease in p57 levels and contribute to tumor cell growth. Furthermore, restoration of p57 levels induced by loss of Jab1 inhibited tumor cell growth and further increased cell apoptosis in HCC cells. Moreover, silencing Jab1 expression further enhanced the antitumor effects of cisplatin-induced apoptosis in HCC cells. Conclusion: Jab1-p57 pathway confers resistance to chemotherapy and may represent a potential target for investigational therapy in HCC.