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)(Cyclin E1、E2)调节细胞周期蛋白依赖性激酶CDK2的活性，从而控制静止期细胞进入细胞周期的S期。因此，Cyclin E/CDK2复合体参与了器官发育和再生的调控，但也可能在肿瘤的发生过程中起着至关重要的作用。大多数肝细胞癌(肝细胞癌)患者表现出Cyclin E1的过度表达。在我们自己的前期工作中，我们提供了强有力的证据，证明Cyclin E1和CDK2在小鼠肝癌模型的发生发展中是必不可少的，而对于肝脏再生和肝脏动态平衡是必不可少的。此外，Cyclin E1对恶性转化的肝细胞的存活和增殖也是必不可少的。对于目前提出的项目，我们假设Cyclin E1和CDK2是治疗肝脏肿瘤的新的、有希望的靶点。该项目的总体目标是在小鼠模型中开发干预方法，分别通过急性切除Cyclin E1或CDK2来抑制或逆转肝癌进展。为此，我们将利用遗传(cre/loxP介导的基因缺失)、药物(CDK抑制剂)和siRNA介导的策略。在前期工作中，我们已经建立了通过siRNA稳定失活小鼠Cyclin E1的新方法。我们将比较Cyclin E1和CDK2抑制肿瘤消退的优缺点，以确定这两个靶点中的哪一个可能最适合肝癌的潜在治疗。此外，我们将验证我们的假设，即肝肿瘤环境中非实质细胞的细胞周期调节和Cyclin E1表达也可能影响肝癌的发生。综上所述，本项目旨在通过有效抑制Cyclin E1/CDK2复合体来开发治疗肝癌的新策略。

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.