FMNL1通过蛋白互作抑制SNAIL降解促进胰腺癌细胞转移的分子机制研究

胰腺导管腺癌（PDAC）是极为恶性的实体肿瘤，患者经诊断后常伴有远端转移，且目前尚无有效的治疗方法。FMNL1是一种细胞骨架调节蛋白，在胚胎发育、组织纤维化及恶性肿瘤发展过程中起重要作用。我们前期预实验结果发现:高表达FMNL1的PDAC细胞株较低表达的细胞株迁移能力更强，而敲低FMNL1的表达后可显著降低PDAC细胞的转移和侵袭效率；我们认为PDAC中异常高表达的FMNL1可与SNAIL蛋白结合抑制其降解再通过EMT通路提高肿瘤细胞转移或侵袭能力。结合前期工作基础，本项目将继续：1）探究FMNL1具体如何与SNAIL蛋白相互作用及具体作用位点；2）蛋白互作如何进一步抑制SNAIL泛素化从而抑制降解的机制。本研究结果将评估其在PDAC中的发展转移中的重要作用，以发现可用于控制PDAC转移的新标靶。

Pancreatic ductal adenocarcinoma (PDAC) is a very malignant solid tumor. Patients often have distant metastases after diagnosis, and there is no effective treatment method. FMNL1 is a cytoskeleton regulatory protein that plays an important role in embryonic development, tissue fibrosis and the development of malignant tumors. Our preliminary experimental results found that: PDAC cell lines with high expression of FMNL1 have stronger migration ability, and knockdown of FMNL1 expression can significantly reduce the transfer and invasion efficiency of PDAC cells; we believe that the abnormally high expression of PDAC FMNL1 can bind to SNAIL protein to inhibit its degradation and then improve tumor cell metastasis or invasion ability through the EMT pathway. Combining the foundation of the previous work, this project will continue to: 1) Explore how FMNL1 interacts with SNAIL protein and the specific sites of action; 2) How protein interactions further inhibit SNAIL ubiquitination and thereby inhibit the mechanism of degradation. The results of this study will evaluate its important role in the development and metastasis of PDAC in order to discover new targets that can be used to control PDAC metastasis.