Kruppel样因子9调控p53表达和诱导肝癌细胞凋亡的分子机制

Kruppel样因子（Kruppel-like factor）参与细胞的多种生物学过程并与多种疾病的发生、发展相关。我们前期研究发现，肝癌组织中转录因子KLF9的表达明显下调或缺失；上调KLF9表达导致肝癌细胞发生凋亡和抑制肝癌细胞的体内生长；提示该基因的功能下调或缺失有利于肝癌的发生和发展。进一步研究还表明，KLF9的表达能够显著提高肿瘤细胞中P53蛋白水平，机制可能涉及KLF9对P53的转录水平和蛋白稳定性的调控。本项目拟在前期发现的基础上，深入研究KLF9与肝癌发生、发展的关系；着重探讨KLF9调控P53和诱导肝癌细胞凋亡的分子机制。此外，我们还将筛选在KLF9诱导细胞凋亡的过程中起关键效应的相互作用蛋白及下游靶基因。本项目将有助于认识转录因子KLF9在肝癌发生和发展中的作用，并可能为新的肝癌治疗策略的设计提供新的靶点和实验依据。

Kruppel-like factors are involved in multiple biological processes, and dysregulation of these proteins is also related to the development of several types of human disease. Our preliminary data have revealed that KLF9 expression is severely down-regulated or lost in human hepatocellular carcinoma (HCC). The forced expression of KLF9 dramatically induces apoptosis and attenuates tumor growth of HCC cells in vivo. Therefore, KLF9 down-regulation may greatly contribute to the development and progression of HCC. Furthermore, KLF9 expression significantly increases the levels of P53 protein in HCC cells possibly through the transcriptional and post-transcriptional mechanisms. Based on these observations, this project will investigate on the relationship between KLF9 and hepatocellular carcinogenesis. We will study the molecular mechanisms underlying KLF9-mediated regulation of P53. Moreover, we will also explore whether p53 or other molecular events is mainly required for KLF9-induced cell apoptosis. This study will identify a relationship between KLF9-initiated cell death and HCC inhibition that may enhance our understanding of human hepatotumorigenesis and lead to the development of novel treatment strategies.