Cyclins and cyclin-dependent kinases: Comparative study of hepatocellular carcinoma versus cirrhosis
Cyclins and cyclin-dependent kinases: Comparative study of hepatocellular carcinoma versus cirrhosis
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DOI：
10.1053/jhep.2003.50112
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发表时间：
2003-03-01
期刊：
影响因子：
13.5
通讯作者：
Kuriyama, S
中科院分区：
文献类型：
--
作者：
Masaki, T;Shiratori, Y;Kuriyama, S
越来越多的证据表明，细胞周期蛋白的紊乱是导致癌症的主要因素之一。本研究的目的不仅是研究肝细胞癌（HCC）中各种细胞周期相关激酶的活性，而且分析丙型肝炎病毒（HCV）诱导的HCC和丙型肝炎病毒诱导的肝硬化中细胞周期相关激酶活性水平的差异。Western blot检测细胞周期蛋白D1、E、A、H及细胞周期蛋白依赖性激酶1 （Cdk1）、Cdk2、Cdk4、Cdk6、Cdk7在HCC及周围非肿瘤性肝硬化组织中的表达水平。采用体外激酶法测定细胞周期蛋白D1、E、A、Cdkl、Cdk4、Cdk6、Cdk7和Weel的酶活性。与周围肝硬化组织相比，HCC中细胞周期蛋白D1、Cdk4、细胞周期蛋白E、细胞周期蛋白A和Weel的蛋白水平和激酶活性显著升高。细胞周期蛋白d1相关激酶活性在HCC中的增强伴随着Cdk4活性的上调，而不是Cdk6活性的上调。Cdk6、Cdk7和Cdk1的激酶活性在HCC和周围肝硬化组织之间没有差异。此外，cyclin D1、Cdk4和cyclin E的蛋白水平和激酶活性在低分化HCC和晚期HCC中较高。综上所述，cyclin D1、Cdk4、cyclin E、cyclin A和Wee I的升高在肝硬化HCC的发生发展中起重要作用。Cyclin D1、Cdk4和Cyclin E的激活可能与HCC的组织病理分级和进展密切相关。
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, Cdkl, Cdk4, Cdk6, Cdk7, and Weel were measured using in vitro kinase assays. Protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin A, and Weel were significantly elevated in HCC compared with surrounding cirrhotic tissues. The enhanced cyclin D I-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 Wee I 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.