Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma
Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma
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DOI：
10.1073/pnas.1807155115
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发表时间：
2018-09-11
影响因子：
11.1
通讯作者：
Liedtke, Christian
中科院分区：
文献类型：
--
作者：
Sonntag, Roland;Giebeler, Nives;Liedtke, Christian
E型细胞周期蛋白E1（CcnE 1）和E2（CcnE 2）是细胞周期蛋白依赖性激酶2（Cdk 2）的调节亚基，被认为控制静止细胞向细胞周期的转变。初步研究结果表明，CcnE 1和CcnE 2在包括肝细胞癌（HCC）在内的几种肿瘤实体中的癌症发展中具有很大程度上重叠的功能。在本研究中，我们分析了CcnE 1、CcnE 2和Cdk 2对小鼠和患者肝癌发生和发展的不同贡献。为此，我们在CcnE 1或CcnE 2组成性缺陷的小鼠以及肝细胞中缺乏Cdk 2的小鼠中测试了HCC易感性。在两种已建立的肝癌模型中，CcnE 1的基因失活在很大程度上防止了小鼠肝癌的发生，而CcnE 2的消融对肝癌发生没有影响。重要的是，CcnE 1驱动的HCC起始依赖于Cdk 2。然而，分离的原发性肝癌细胞通常在体外随着进展的增加而获得对CcnE 1和Cdk 2的独立性，这与涉及CcnE 2的二次诱导和细胞周期和DNA修复途径的上调的基因签名相关。重要的是，在具有升高的CcnE 2表达和低生存率的HCC患者中也发现了类似的表达谱。总的来说，HCC患者的总生存率受CcnE 1和CcnE 2表达的协同影响，但不受Cdk 2的影响。我们的研究表明，肝癌的发生特别依赖于CcnE 1和Cdk 2，而肝癌的进展需要任何E-cyclin的表达，但没有Cdk 2。
E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnEl and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.