Cyclins and cyclin-dependent kinases: comparative study of hepatocellular carcinoma versus cirrhosis.
Increasing evidence has indicated that perturbation of cyclins is one of the major factors leading to cancer. The aim of this study was not only to investigate various cell cycle-related kinase activities in hepatocellular carcinoma (HCC), but also to analyze the difference of cell cycle-related kinase activity levels between hepatitis C virus (HCV)-induced HCC and HCV-induced cirrhosis. The protein levels of cyclins D1, E, A, and H, and of cyclin dependent kinase 1 (Cdk1), Cdk2, Cdk4, Cdk6, and Cdk7 in HCC and in surrounding nontumorous cirrhosis were determined by Western blot. The enzymatic activities of cyclins D1, E, A, Cdk1, Cdk4, Cdk6, Cdk7, and Wee1 were measured using in vitro kinase assays. Protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 were significantly elevated in HCC compared with surrounding cirrhotic tissues. The enhanced cyclin D1-related kinase activity in HCC was accompanied by the up-regulation of Cdk4 activity, but not Cdk6 activity. The kinase activities of Cdk6, Cdk7, and Cdk1 did not differ between HCC and surrounding cirrhotic tissues. In addition, the protein levels and kinase activities of cyclin D1, Cdk4, and cyclin E were higher in poorly differentiated HCC and advanced HCC. In conclusion, the increases of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 play an important role in the development of HCC from cirrhosis. Cyclin D1, Cdk4, and cyclin E activation may be closely related to the histopathologic grade and progression of HCC.
Masaki
Tsutomu
T
Third Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan. tmasaki@kms.ac.jp
Shiratori
Yasushi
Y
Rengifo
William
W
Igarashi
Kouichi
K
Yamagata
Michiko
M
Kurokohchi
Kazutaka
K
Uchida
Naohito
N
Miyauchi
Yoshiaki
Y
Yoshiji
Hitoshi
H
Watanabe
Seishiro
S
Omata
Masao
M
Kuriyama
Shigeki
S
D000368:Aged; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000032:analysis / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D019925:Cyclin A / Q000032:analysis / Q000378:metabolism; D019938:Cyclin D1 / Q000032:analysis / Q000378:metabolism; D019927:Cyclin E / Q000032:analysis / Q000378:metabolism; D056748:Cyclin H; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000032:analysis* / Q000378:metabolism; D016213:Cyclins / Q000032:analysis* / Q000378:metabolism; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D000095043:Cyclin-Dependent Kinase-Activating Kinase
C534751:CCNH protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D019927:Cyclin E; D056748:Cyclin H; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722413:CCRK protein, human; C000722416:CDK7 protein, human