p53新的靶基因PRWP抑制肿瘤细胞迁移的作用及机制研究

The tumor suppressor p53 plays a pivotal role in the protection against cancer. In the development of more than half of human tumors, p53 is frequently inactivated by oncogenic mutations. It has been increasingly recognized that p53 is able to inhibit cancer cell migration, however, the underlying mechanisms remain uncertain. Our research aims to address this issue. Our preliminary data show that as a novel potential p53 target gene, PRWP (p53-regulated WD40 repeat domain-containing protein) is capable of inhibiting cancer cell migration. In addition, PRWP interacts with the Arp2/3 complex, a nucleation core for de novo actin polymerization. Furthermore, ectopic expression of PRWP impairs the recruitment of Arp2 to plasma membrane upon EGF stimulation. These results imply that PRWP may inhibit cancer cell migration via binding to the Arp2/3 complex and regulating Arp2/3-mediated actin nucleation and polymerization. In this study, we will further investigate the molecular mechanism of PRWP-inhibited cancer cell migration. Additionally, we will evaluate whether PRWP could mediate p53's function in the regulation of cancer cell migration. We will also explore the possible role of PRWP in cancer initiation and progression. This study will generate novel insights into the mechanisms whereby Arp2/3-mediated actin polymerization is dysregulated during cancer cell migration. This may also advance our understanding of how p53 exerts its tumor suppressive activities.

p53作为抑癌蛋白在肿瘤发生发展过程中起着关键的调控作用。虽然p53抑制肿瘤细胞迁移的功能已被人们逐渐认识，然而其潜在的分子机制目前仍然不是很明确。本项目以此为研究切入点，我们前期的研究结果表明，作为p53的一个新的潜在靶基因，PRWP能够抑制肿瘤细胞的迁移；它可以和微丝成核关键因子Arp2/3复合体发生相互作用，并能够抑制表皮生长因子EGF诱导的Arp2向细胞膜的转移；这暗示PRWP可能通过结合Arp2/3复合体并调控其介导的微丝聚合过程，最终抑制肿瘤细胞的迁移能力。本项目将在已有的工作基础上，进一步深入研究PRWP抑制肿瘤细胞迁移的作用和机制；研究PRWP是否介导或部分介导p53对肿瘤细胞迁移的调控功能；同时也将研究其在肿瘤发生发展特别是肿瘤转移中的作用。这将有助于拓展人们对Arp2/3介导的微丝聚合在肿瘤细胞迁移中的功能及调控机制的认识，并加深人们对p53发挥抑癌功能分子基础的理解。

p53作为抑癌蛋白在肿瘤发生发展过程中起着关键的调控作用。虽然p53抑制肿瘤细胞迁移的功能已被人们逐渐认识，然而其潜在的分子机制目前仍然不是很明确。本项目以此为研究切入点，我们的研究鉴定了一个新的受p53转录上调的靶基因WDR63。在功能上，WDR63能够抑制肿瘤细胞的迁移和侵袭能力，并在小鼠体内抑制肿瘤的肺转移。在分子机制层面，WDR63能够和微丝成核关键因子Arp2/3复合体发生相互作用，并抑制Arp2/3介导的分支状微丝的聚合过程。更为重要的是，WDR63能够介导p53对肿瘤转移的抑制作用。另外，与正常组织相比，肺腺癌和肺鳞癌中的WDR63呈现低表达的状态；WDR63在肺腺癌和肺鳞癌中的表达水平和p53的突变状态具有显著相关性；WDR63的低表达和肺鳞癌的恶性程度也具有很好的相关性。这些研究结果不仅拓展了人们对Arp2/3复合体介导的微丝聚合在肿瘤转移中的功能及调控机制的认识，还暗示WDR63在p53抑制肿瘤转移的过程中发挥了重要的介导作用。在本项目的大力资助下，项目负责人以通讯作者的身份在PNAS、EMBO Reports和Oncogene等国际主流期刊上发表SCI学术论文6篇。