癌蛋白Cdc20促进食管癌细胞增殖的机制研究

Esophageal cancer (EC) is one of common gastrointestinal tumors that cause deaths in patients. The molecular mechanism of esophageal tumorigenesis is unclear. High expression of oncoprotein Cdc20 has been observed in a variety of human cancers. However, it is elusive how Cdc20 is critically involved in EC development and progression. Our previous study showed that downregulation of Cdc20 by its siRNA inhibited cell growth and induced G2/M arrest in EC cells. Importantly, depletion of Cdc20 increased the expression of FOXO1. Overexpression of FOXO1 inhibited cell growth in EC. Moreover, we found that Cdc20 could bind to FOXO1 by our IP assay. These data suggest that FOXO1 could be a substrate of Cdc20. In this proposal, we will explore whether Cdc20 exerts its oncogenic function via ubiquitination and degradation of FOXO1 in EC. To test our hypothesis, we will perform several approaches such as FACS, transwell, Western-blot, Co-IP, RT-PCR, and transfection in vitro and in vivo. We also investigate whether Cdc20 is involved in cisplatin resistance via regulation of FOXO1 in EC. Our current proposal will explore the role of Cdc20 and FOXO1 via multiple study levels, which could provide the new direction for the prevention and treatment of EC.

食管癌是肿瘤相关性死亡的常见原因，其恶性进展的分子机制仍不清楚。癌蛋白Cdc20在多种肿瘤中异常高表达，但在食管癌中的作用尚不明确。我们在预实验中发现：敲除Cdc20可以抑制食管癌生长、导致G2/M期阻滞、FOXO1表达升高；过表达FOXO1后癌细胞增殖抑制；IP实验进一步发现Cdc20与FOXO1相互结合。据此我们提出假说：FOXO1是Cdc20的新靶点，Cdc20通过泛素化降解FOXO1的表达而促进食管癌生长和转移。为验证该假说，拟在食管癌临床标本和细胞株中采用流式、transwell、Western-blot、Co-IP、RT-PCR、基因沉默/过表达等手段，阐明Cdc20如何通过FOXO1在食管癌中发挥癌基因的作用，并进行动物模型验证，最后探讨Cdc20和FOXO1在顺铂耐药中的作用。本研究从Cdc20通过FOXO1促进食管癌恶性进展的新视点进行多层次探讨，为食管癌防治提供新方向。

食管癌是肿瘤相关性死亡的常见原因，其恶性进展的分子机制仍不清楚。癌蛋白Cdc20在多种肿瘤中异常高表达，但在食管癌中的作用尚不明确。本项目从临床标本、细胞、组织、动物实验四个层面探讨Cdc20和FOXO1在食管癌中的作用，揭示了Cdc20在食管癌中发挥致癌因子的作用，而FOXO1可能在食管癌的生长中发挥抑癌因子的作用；探讨了FOXO1是Cdc20的底物，Cdc20可以通过调控FOXO1而发挥促食管癌的作用；提出并验证了“FOXO1可能是Cdc20的新靶点，Cdc20通过调控FOXO1的表达而促进食管癌的生长和转移”的科学假设；并提出Cdc20及FOXO1有望成为食管癌治疗的潜在新靶点。项目实施过程中，发表论文4篇，其中SCI论文2篇（影响因子均>5分）；培养硕士研究生2名；团队成员完成正高职称晋升1人；申请专利2项；参加国际学术交流2次、国内学术交流数次；通过项目开展锻炼了团队、提高了团队的科研实力，为进一步开展基础-临床转化型研究打下坚实基础。