CDK10通过ETS2控制Snail转录干预食管鳞癌EMT和转移起始的分子机制

Esophageal squamous cell carcinoma (ESCC) carries a poor prognosis that is largely attributable to metastasis, in which epithelial-mesenchymal transition (EMT) is one essential mechanism that occurs at the initial stage. However, the underlying molecular mechanism remains to be elucidated. We have indicated cyclin-dependent kinase 10 (CDK10) as a candidate tumor suppressor. Our latest results reveal that ① CDK10 protein levels were significantly decreased in metastatic ESCC tissues; ② silencing CDK10 expression enhanced malignant invasiveness of ESCC cells; and ③ the expression of EMT-related proteins were closely associated with CDK10. We thus hypothesize that CDK10 is one of the important genes to regulate EMT and metastasis initiation of ESCC. Based on our original preliminary work, we are going to investigate the molecular mechanism of CDK10 on ESCC metastasis by ① exhibiting the effect of CDK10 to modulate metastasis initiation steps using in intro cell culture experiments; ② evaluating whether CDK10 is the switch to control metastasis using in vivo tumor metastasis models and fluorescence imaging technology; ③ demonstrating that CDK10 suppresses Snail transcription via ETS2 to prevent EMT and metastasis initiation; and ④ examining clinical specimens to illustrate the potential relationship between CDK10 expression and ESCC metastasis and prognosis. Collectively, the present study aims at the initial stage of ESCC metastasis and investigates the functions and molecular mechanism of CDK10, which might offer us a novel strategy to prevent ESCC metastasis from its initiation stage.

上皮-间质转化（EMT）在食管鳞癌转移起始阶段发挥着重要作用，然而其分子调控机制尚不清晰。申请人证实周期素依赖性激酶10（CDK10）是潜在的抑癌基因，前期研究发现：①已有转移食管鳞癌组织中CDK10表达显著下调；②沉默CDK10增强食管鳞癌细胞恶性侵袭能力；③CDK10与EMT关键蛋白表达密切相关。据此推测CDK10是调控食管鳞癌EMT和转移起始的重要基因。本课题在原创性前期工作基础上：①应用体外细胞实验明确CDK10对转移起始关键步骤的调节；②活体成像技术结合裸鼠转移模型，动态分析CDK10是控制食管鳞癌转移的开关；③证实通过ETS2控制Snail转录是CDK10干预EMT和转移起始的分子机制；④检查临床标本，研究CDK10表达与食管鳞癌转移和预后的关系。本课题针对转移的起始环节，探讨CDK10在食管鳞癌转移中的作用和分子机制，将为从源头遏制食管鳞癌转移提供理论基础。

我国是食管鳞状上皮细胞癌（简称食管鳞癌）的高发国家之一，转移是导致食管鳞癌临床治疗失败和病人死亡的最主要原因。已知上皮-间质转化（epithelial-mesenchymal transition，EMT）是转移起始过程中的关键环节，阻断EMT有可能成为干预食管鳞癌转移的有效途径。然而，目前关于食管鳞癌EMT的分子调控机制尚不清晰。本项目依据原创性前期工作，针对转移的起始环节，解析引发食管鳞癌转移的源头机制，旨在阐明细胞周期素依赖性激酶10（cyclin-dependent kinase 10，CDK10）是调控食管鳞癌EMT和转移起始的重要基因并探讨相应的分子机制：①应用体外细胞培养系统明确了CDK10对食管鳞癌转移起始关键步骤的调节，CDK10表达变化影响食管鳞癌EMT功能表型和细胞迁移侵袭能力；②证实了CDK10调控食管鳞癌EMT和转移起始的分子机制，CDK10通过调节EMT标志分子表达干预食管鳞癌转移起始，通过高通量基因芯片和生物信息学分析筛选出CDK10调控转移相关信号通路的关键分子；③检查食管鳞癌临床标本揭示了CDK10表达与食管鳞癌转移和预后的关系，食管鳞癌组织中CDK10表达同T分期、临床TNM分期、淋巴结转移显著相关，是影响患者总生存期的独立预后指标。本项目对于阐明食管鳞癌转移的分子机理和开发新的抗转移药物具有重要意义，将为从源头遏制食管鳞癌转移提供理论基础。受本项目资助，培养硕士研究生2人，发表研究论文8篇，其中SCI收录6篇。