title: Down-regulation of the cyclin-dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis.
abstract: 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.
  
  
  CONCLUSIONS
  Jab1-p57 pathway confers resistance to chemotherapy and may represent a potential target for investigational therapy in HCC.
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Jing
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Yangzi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Division of Critical Care Medicine & Pulmonary Services, University of Athens School of Health Sciences, Athens, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Atsaves
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.|Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Rujuan
authors.initials: R
authors.lastname: Su
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Yamin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pathology and Cytology, Karolinska University Hospital & Karolinska Institute, Stockholm, Sweden.
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, P. R. China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Nan
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Experimental Therapeutics Academic Program and Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX.
authors.forename: Francois X
authors.initials: FX
authors.lastname: Claret
mesh_terms: D000818:Animals; D000075686:COP9 Signalosome Complex; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D047908:Intracellular Signaling Peptides and Proteins; D044786:S-Phase Kinase-Associated Proteins; D051057:Proto-Oncogene Proteins c-akt; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D002945:Cisplatin