p53-AKT网络平衡失控存在于绝大多数恶性肿瘤，发现其关键的调控节点对于发现新药物靶点和发展新型治疗方法有重要意义。我们前期结果提示，RARγ及其新型拮抗剂刺槐素对该网络的平衡机制有显著影响，这是一个新的发现。本项目将系统研究RARγ驱动的p53-AKT网络促癌作用，重点研究RARγ直接作用于p53、诱导其出核和作用于其泛素-蛋白酶体降解系统，AKT及不同亚型活性对此过程的影响，确定RARγ、p53和AKT之间直接和间接相互作用，阐述其影响因素和信号转导机制，确定刺槐素的衍生物与RARγ结合及逆转p53-AKT网络促癌的分子机制，阐述RARγ在p53-AKT网络中促癌/抑癌相互转换的分子开关角色，通过开展肝癌临床标本分析和动物实验，探讨RARγ依赖p53-AKT网络机制在肝癌中潜在的病理学意义，提出抗肿瘤药物新通路和新靶点，并为这类黄酮类先导物的优化与改进提供重要理论基础。

The deregulation of p53-AKT network is closely associated with most of malignant tumors. It is critical for finding new regulators of this balance to discover new drug targets and develop new therapeutic methods. Our pilot study indicates that this balance can be potently regulated by RARγ and its newly identified antagonists acacetin and analogs, which is not yet reported by others. In this study, we will systemically investigate the underlying mechanism by which the pro-tumorigenesis effect of p53-AKT driven by RARγ, focusing on studying the roles of RARγ in inducing p53 nuclear export and its ubiquitinoylation through direct or indirect interaction. We will also document how AKT and subtypes are involved in these processes. In addition, we will further confirm the binding activity acacetin analogs on RARγ and explore their roles in inhibiting the pro-tumorigenesis effect of RARγ dependent p53-AKT network through targeting to RARγ. From these processes, we will be able to see whether RARγ is a molecular switcher of p53-AKT balance. We will finally study the clinical HCC samples and conduct animal experiments to disclose the pathophysiological significance and drug target value of RARγ dependent p53-AKT network. Our finding will also provide a new basis for improving the acacetin leads.