Nur77是一种孤儿核受体，它能够对细胞应激作出快速应答反应，在许多肿瘤中高表达。肝癌中HBx是一种关键的致癌蛋白，肿瘤中大量的TNFa是维持肿瘤微环境炎症反应和肿瘤细胞恶性进展的关键调控者，二者在肝癌的发生发展中具有显著的协同作用，但其调控机制仍不清楚。我们前期发现，HBx可以与Nur77直接相互作用，HBx诱导GSK-3b活性可调控二者的相互作用。本项目将在此基础上，重点研究Nur77在HBx和TNFa系统中的生存机制和信号转导，并利用Nur77调控化合物，研究其生存与死亡的转换机制，阐述HBx、TNFa和Nur77在肝癌中的交互作用和信号转导，以揭示肝癌新的发病机制，鉴定新药物靶标，并为发展新的肝癌防治方法提供理论依据。

Nur77, an orphan nuclear receptor, can quickly respond to various stress stimuli. It is demonstrated that Nur77 is elevated in a number of different tumors. HBx plays critical roles in the development of hepatocellular carcinoma (HCC). TNFa, largely produced in the tumor microenvironment, is a key factor for tumor-associated inflammatory response and confers to tumor aggressive behavior. HBx and TNFa can synergistically impact on the growth of HCC with unknown mechanism. Our preliminory results have shown that HBx can directly interact with Nur77, which can be regulated by GSK-3b. Based on it, we will further investigate the survival action and regulation of Nur77 by HBx and TNFa, and explore the mechanism of "survival and death" switch by Nur77 when targeted by certain compounds. This study is thus expected to disclose the signaling interplay of HBx, TNFa and Nur77 in HCC, to identify new therapeutic targets, and to provide theoretical basis for developing new anticancer strategies.