Down-Regulation of the Cyclin-Dependent Kinase Inhibitor p57 Is Mediated by Jab1/Csn5 in Hepatocarcinogenesis

被引:47
作者
Guo, Hui [1 ,2 ]
Jing, Li [1 ]
Cheng, Yangzi [1 ]
Atsaves, Vassilis [3 ]
Lv, Yi [1 ,4 ]
Wu, Tao [1 ]
Su, Rujuan [1 ]
Zhang, Yamin [1 ]
Zhang, Ronghua [2 ]
Liu, Wenbin [5 ]
Rassidakis, George Z. [6 ,7 ]
Wei, Yongchang [1 ]
Nan, Kejun [1 ]
Claret, Francois X. [2 ,8 ,9 ]
机构
[1] Xi An Jiao Tong Univ, Coll Med, Affiliated Hosp 1, Dept Oncol, Xian, Peoples R China
[2] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA
[3] Univ Athens, Sch Hlth Sci, Dept Med, Div Crit Care Med & Pulm Serv, Athens, Greece
[4] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Xian, Peoples R China
[5] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA
[6] Karolinska Univ Hosp, Dept Pathol & Cytol, Stockholm, Sweden
[7] Karolinska Inst, Stockholm, Sweden
[8] Univ Texas Grad Sch Biomed Sci Houston, Expt Therapeut Acad Program, Houston, TX USA
[9] Univ Texas Grad Sch Biomed Sci Houston, Canc Biol Program, Houston, TX USA
基金
美国国家卫生研究院; 中国国家自然科学基金;
关键词
DOMAIN-BINDING PROTEIN-1; HUMAN HEPATOCELLULAR-CARCINOMA; P57(KIP2) PROTEOLYSIS; COP9; SIGNALOSOME; P27; EXPRESSION; CANCER; ACTIVATION; OVEREXPRESSION; DEGRADATION; P27(KIP1);
D O I
10.1002/hep.28372
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
引用
收藏
页码:898 / 913
页数:16
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