Therapy of Hepatocellular Carcinoma through targeted inhibition of the cell cycle mediators Cyclin E1 and Cdk2 in mouse models

E-细胞周期蛋白（Cyclin E1，E2）调节细胞周期蛋白依赖性激酶Cdk 2的活性，从而控制静止细胞向细胞周期S期的转变。因此，细胞周期蛋白E/Cdk 2复合物参与器官发育和再生的控制，但也可能在癌变过程中发挥关键作用。大多数肝细胞癌（HCC）患者表现出细胞周期蛋白E1的过度表达。在我们自己的初步工作中，我们提供了强有力的证据表明，细胞周期蛋白E1和Cdk 2是必不可少的肝癌的发展在小鼠模型中，而他们是肝再生和肝脏稳态。此外，至少细胞周期蛋白E1也是恶性转化肝细胞的存活和增殖所必需的。对于目前提出的项目，我们假设细胞周期蛋白E1和Cdk 2是新的，有前途的目标，用于治疗肝肿瘤。该项目的总体目标是在小鼠模型中开发干预方法，分别通过细胞周期蛋白E1或Cdk 2的急性消融来抑制或逆转HCC进展。为此，我们将利用遗传（cre/loxP介导的基因缺失），药理学（Cdk抑制剂）和siRNA介导的策略。在前期工作中，我们已经建立了新的方法，通过siRNA在小鼠中稳定失活细胞周期蛋白E1。我们将比较细胞周期蛋白E1与Cdk 2抑制肿瘤消退的优点和缺点，以确定这两个目标中的哪一个可能最适合用于HCC的潜在治疗。此外，我们将测试我们的假设，即细胞周期调控和细胞周期蛋白E1的表达在非实质细胞的肝肿瘤环境也可能影响肝癌的发生。总之，本项目旨在开发新的策略，通过有效抑制细胞周期蛋白E1/Cdk 2复合物来治疗HCC。

E-cyclins (Cyclin E1, E2) regulate the activity of the cyclin-dependent kinase Cdk2 and thereby control the transition of quiescent cells into the S-phase of the cell cycle. Therefore, the Cyclin E/Cdk2 complex is involved in the control of organ development and regeneration, but may also have a crucial role during carcinogenesis. The majority of patients with Hepatocellular Carcinoma (HCC) show over-expression of Cyclin E1. In own preliminary work we provided strong evidences that Cyclin E1 and Cdk2 are essential for the development of HCC in mouse models, while they are dispensable for liver regeneration and liver homeostasis. In addition, at least Cyclin E1 is also essential for survival and proliferation of malignant transformed hepatocytes. For the present proposed project we hypothesize that Cyclin E1 and Cdk2 are novel, promising targets for the therapy of liver tumors. The overall aim of this project is the development of interventional approaches in mouse models for the inhibition or reversion of HCC progression by acute ablation of Cyclin E1 or Cdk2, respectively. To this end we will take advantage of genetic (cre/loxP mediated gene deletion), pharmacological (Cdk inhibitors) and siRNA-mediated strategies. In preliminary work we already established novel methods for stable inactivation of Cyclin E1 through siRNA in mice. We will compare the advantages and disadvantages of Cyclin E1 versus Cdk2 inhibition for the tumor regression in order to define which of the two targets might be most suitable for a potential therapy of HCC. In addition we will test our hypothesis that cell cycle regulation and Cyclin E1 expression in non-parenchymal cells of the hepatic tumor environment may also affect hepatocarcinogenesis. In summary the present project aims to develop novel strategies to cure HCCs by effective inhibition of the Cyclin E1/Cdk2 complex.