【摘要】 背景:整合素α_vβ₆在多种肿瘤细胞上高表达,能促进肿瘤细胞的异常增殖和恶性转移。整合素α_vβ₆通过与配体纤连蛋白的相互作用介导了肿瘤细胞的黏附与迁移,该过程不仅受到整合素α_vβ₆与纤维蛋白相互作用强弱的影响,也受到血流环境下剪应力的调节。因此,揭示整合素α_vβ₆和纤连蛋白相互作用的力-化学调控机制具有重要的理论意义和应用价值。目的:通过定量化力条件下整合素α_vβ₆与纤连蛋白的相互作用,揭示蕴含在黏附现象背后的力调控机制。方法:在不同剪切力下,驱使包被纤连蛋白RGD片段的微球在铺有整合素α_vβ₆的底板上黏附,观察和记录该黏附现象,获取黏附微球的瞬时速度和累积距离随时间变化的曲线,提取生存时间和解离速率参数。结果与结论:整合素α_vβ₆与纤连蛋白片段相互作用存在流动增强型现象,随着流体剪切力的增加,两者相互作用的键生存时间出现先增加后减少趋势。相反,随流体剪切力的增加,键解离速率出现先减小后增加趋势。该力依赖的生存时间和逆反应速率的双态性表明,整合素α_vβ₆与纤连蛋白片段介导的流动增强型现象是由逆锁键所调控的。更多还原

【Abstract】 BACKGROUND: Integrin α_vβ₆ is highly expressed on cancer cells and promotes abnormal proliferation and malignant metastasis of cancer cells. Integrin α_vβ₆ mediates the adhesion and migration of tumor cells through interacting with its ligand, fibronectin. This process is not only regulated by the interaction between integrin α_vβ₆ and fibronectin, but also adjusted by shear stress under blood flow. Therefore, it is significant to study the force-chemical mechanism of integrin α_vβ₆-fibronectin interaction. It will further our understanding of the process of malignant metastasis, and benefit the design of novel α_vβ₆-targeted drugs. OBJECTIVE: To reveal the force-regulated mechanism of cell adhesion, interaction between integrin α_vβ₆ and fibronectin was quantified under fluid shear stress. METHODS: The adhesive behaviors of microspheres coated with RGD fibronectin fragment on the integrin α_vβ₆-coated substrate under different shear forces were observed and recorded. To study the mechanism of integrin α_vβ₆ interacting with fibronectin, the lifetime and dissociation rate of integrin α_vβ₆-fibronectin bond were extracted from the instantaneous velocity-time and cumulative distance-time graphs. RESULTS AND CONCLUSION: Flow-enhanced phenomenon of integrin α_vβ₆ interacting with fibronectin fragments was observed. Bond lifetime of integrin α_vβ₆-fibronectin increased first and then decreased as fluid shear force increased, while the bond dissociation rate decreased first and then increased. As the fluid shear force increased, the bond dissociation rate decreased first and then increased. The force-dependent lifetime and dissociation rate of integrin α_vβ₆-fibronectin bond showed that the flow-enhanced adhesion phenomenon was regulated by catch-bond mechanism.更多还原