"MBD1-Stathmin-微管稳定"调控上皮间质转化影响胰腺癌侵袭转移的实验研究

Epithelial-Mesenchymal Transition（EMT）is a crucial process whereby pancreatic cancer(PC) cells acquire high invasive and metastatic potentials. Disruption of EMT could suppress human pancreatic carcinoma progression and improve the poor prognosis. Our previous studies demonstrate that (1) Methyl-CpG Binding Domain Protein 1(MBD1) promotes EMT process in some of PC cells; (2) Paradoxically, MBD1 loses its effects on EMT in PC cells where Stathmin, a microtubule-destabilizing protein, is silent; (3) High-throughput proteomic analysis and low-throughput validation show that the expression of MBD1 is in concert with Stathmin in PC cell lines as well as clinical tissue samples. Therefore, MBD1 could achieve an elaborate regulation on EMT process that is dependent on a Stathmin-related microtubule dynamics in PC. Accordingly, in this study, we aim to unmask the specific mechanisms of a "MBD1-Stathmin- microtubule dynamics" functional axis modulates EMT process, develop an effective clinical intervention target or prognostic/predictive factor, as well as provide an in-depth insight into PC metastatic profiles.

上皮-间质转化(EMT)是胰腺癌细胞获得高侵袭转移特性的重要过程，阻止上皮-间质转化，就有可能减少胰腺癌侵袭转移，改善预后。我们前期研究证明：（1）甲基化结合域蛋白MBD1可调控部分胰腺癌细胞系的EMT进程；（2）但对于微管不稳定蛋白Stathmin低表达的胰腺癌细胞系，MBD1则失去对EMT的调控作用；（3）高通量蛋白质谱分析及低通量验证表明，胰腺癌细胞和组织中MBD1与Stathmin的表达呈正相关。因此，MBD1可能依赖"Stathmin-微管稳态"实现对胰腺癌EMT的精确调控。本课题基于此，研究"MBD1-Stathmin-微管稳态"功能轴调控上皮-间质转化、进而影响胰腺癌侵袭转移特性的具体机制与过程，并建立有效的临床预测模型和干预靶点，为深入了解胰腺癌的转移特性、进一步指导临床提供依据。

上皮-间质转化(EMT)是胰腺癌发生侵袭转移的重要过程，深入研究胰腺癌侵袭转移的具体分子机制，可能为胰腺癌的治疗提供新的思路和线索，改善预后。本项目主要研究“MBD1-Stathmin-微管稳态”功能轴调控上皮-间质转化（EMT）、进而影响胰腺癌侵袭转移特性的具体机制与过程，并建立有效的临床预测模型和干预靶点。本课题按照研究计划和内容，首先对Stathmin这个关键分子和EMT进行了系统性文献回顾并发表综述。同时，我们发现Stathmin可以通过调控NF-κB信号通路，促进胰腺癌上皮间质转化和侵袭转移。在研究和分析胰腺癌侵袭转移可能机制时，我们还发现MBD1-LSD1通路，Kras-MUC16通路以及免疫微环境异常等可能与胰腺癌高侵袭转移相关。另外，我们创新性的鉴定出“CA199假阴性”胰腺癌亚群，具有高侵袭转移特征。以上研究结果可能为胰腺癌的治疗提供新的分子靶点和研究思路。