In egress routes of malignancy, cancer cells are constantly subjected to shear stress imposed by blood/lymph flow. Increasing evidence points toward the regulatory roles of shear stress in tumor cell adhesion and motility. Although it is known that integrin endocytic trafficking governs focal adhesion (FA) turnover and cell migration, the effect and biological consequences of low shear stress (LSS) on integrin trafficking remain unclear. Here, we identified the critical role of integrin β1 trafficking and caveolin-1 (Cav-1) mediated endocytosis in LSS-induced cell directional migration. LSS altered the distribution of integrin β1 in MDA-MB-231 cells and significantly promoted its internalization and recycling, which in turn facilitated FA turnover and directional cell migration. Furthermore, LSS induced cytoskeleton remodeling, which was required for internalization of integrin β1. LSS down-regulated the acetylation level of microtubules (MTs) via activating ROCK/HDAC6 pathway, resulting in elevation of MTs dynamics, Cav-1 motility, and Cav-1-dependent integrin β1 recycling. We also showed that high HDAC6 expression was a ROCK-dependent prognostic factor, which was correlated with poor outcomes in breast cancer patients. Taken together, these results defined a novel mechanism by which LSS enhanced integrin β1 trafficking via actin cytoskeleton remodeling and ROCK/HDAC6 mediated deacetylation of MTs, thereby promoting FAs turnover and directional cell migration.

中文翻译：

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剪应力通过促进微管的脱乙酰作用刺激整联蛋白β1的运输并增加癌细胞的定向迁移。

在恶性肿瘤的排出途径中，癌细胞不断受到血液/淋巴液流施加的剪切应力。越来越多的证据表明剪切应力在肿瘤细胞粘附和运动中的调节作用。尽管已知整联蛋白内吞运输控制粘着（FA）转换和细胞迁移，但低剪切应力（LSS）对整联蛋白运输的影响和生物学后果仍不清楚。在这里，我们确定了整合素β1转运和caveolin-1（Cav-1）介导的内吞作用在LSS诱导的细胞定向迁移中的关键作用。LSS改变了整联蛋白β1在MDA-MB-231细胞中的分布，并显着促进了其内在化和再循环，进而促进了FA的更新和细胞的定向迁移。此外，LSS诱导了细胞骨架重塑，这是整合素β1内在化所必需的。LSS通过激活ROCK / HDAC6途径下调了微管（MTs）的乙酰化水平，导致MTs动力学，Cav-1活力和Cav-1依赖性整联蛋白β1循环的升高。我们还表明，高HDAC6表达是ROCK依赖的预后因素，与乳腺癌患者的不良预后相关。综上所述，这些结果定义了一种新的机制，LSS通过肌动蛋白细胞骨架重塑和ROCK / HDAC6介导的MT脱乙酰基增强了整联蛋白β1的运输，从而促进了FAs的更新和定向细胞的迁移。和依赖Cav-1的整合素β1回收。我们还表明，高HDAC6表达是ROCK依赖的预后因素，与乳腺癌患者的不良预后相关。综上所述，这些结果定义了一种新的机制，LSS通过肌动蛋白细胞骨架重塑和ROCK / HDAC6介导的MT脱乙酰基增强了整联蛋白β1的运输，从而促进了FAs的更新和定向细胞的迁移。和依赖Cav-1的整合素β1回收。我们还表明，高HDAC6表达是ROCK依赖的预后因素，与乳腺癌患者的不良预后相关。综上所述，这些结果定义了一种新的机制，LSS通过肌动蛋白细胞骨架重塑和ROCK / HDAC6介导的MT脱乙酰基增强了整联蛋白β1的运输，从而促进了FAs的更新和定向细胞的迁移。