3D基质硬度通过COX-2介导炎症反应促进结肠癌EMT的机制研究

细胞外基质硬化是肿瘤发生上皮间质转化（EMT）的关键诱因之一，但其调控机制尚不清楚。本课题基于可独立调节硬度的3D细胞培养体系，研究发现COX-2介导的炎症反应是基质硬度促进结肠癌EMT的关键环节，靶向COX-2可能是阻断基质硬化/炎症/EMT轴的有效途径。申请人进一步研究发现，COX-2与酪氨酸激酶FYN及其脚手架分子CAV1结合。由于CAV1参与感受胞外机械力，推测硬性基质使得COX-2与CAV1/FYN形成复合物并被磷酸化激活，进而驱动结肠癌细胞的炎症反应，最终导致EMT的发生。. 本研究旨在阐明COX-2响应基质硬度并驱动炎症反应诱导EMT的分子机制，将细胞外机械力信号与肿瘤的侵袭转移行为相耦连；提出靶向COX-2阻断基质硬度/炎症/EMT轴限制结肠癌转移的治疗策略，为临床应对结肠癌转移和复发提供全新思路和理论依据。

Prevention and cure of tumor metastasis is the key point of clinical treatment of colon cancer since metastasis is the main cause of death, but there are many challenges. Tumor development is often accompanied by extracellular matrix sclerosis, which induces epithelial mesenchymal transition (EMT) of tumor cells and activates metastasis cascade, but the specific mechanism is still unclear. In this study, we found that COX-2 mediated inflammatory response is the key event of matrix stiffness promoting EMT of colon cancer, and targeting COX-2 may be an effective way to block the Matrix stiffness/Inflammation/EMT axis. Further studies showed that COX-2 binds to tyrosine kinase FYN and its scaffold molecule CAV1. Because CAV1 is involved in the perception of extracellular mechanical force, it is speculated that the stiff matrix makes COX-2/CAV1/FYN form a complex and COX-2 is then activated by phosphorylation, which drives the inflammation of colon cancer cells and eventually leads to EMT. This study aims to elucidate the molecular mechanism of COX-2 in response to matrix stiffness and inflammation, and to couple extracellular mechanical signal with tumor invasion and metastasis behavior, so as to provide a new perspective for the prevention and treatment of colon cancer metastasis.