Circulating Tumor Cell Migration Requires Fibronectin Acting through Integrin B1 or SLUG
Circulating Tumor Cell Migration Requires Fibronectin Acting through Integrin B1 or SLUG
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DOI：
10.3390/cells9071594
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发表时间：
2020-07-01
期刊：
影响因子：
6
通讯作者：
Ogunwobi, Olorunseun O.
中科院分区：
文献类型：
--
作者：
Huaman, Jeannette;Ogunwobi, Olorunseun O.
纤连蛋白（FN 1）是一种细胞外基质蛋白，因其在癌症进展中的多方面作用而日益受到关注。使用我们最近建立的循环肿瘤细胞（CTC）系，我们已经证明，与原发性肿瘤细胞系相比，CTC系中FN1表达增加，迁移增强。增加的FN1表达是否是CTC迁移的直接需要，以及FN1调节整合素B1（ITGB1）和SLUG（SNAI2）在CTC迁移中的具体作用仍不清楚。在这里，我们第一次报道了CTC中FN1、ITGB1或SLUG表达的敲低导致CTC迁移的显著减少。同时敲除两种或所有三种蛋白质并不能进一步抑制迁移。我们观察到当将重组FN1加入CTC中时，CTC迁移相应增加。这种作用被ITGB1或SLUG的预先敲低显著阻碍。通过敲除实验和蛋白质印迹分析，我们证实了FN1对ITGB1和SLUG的调节是通过两条独立的途径发生的。因此，我们可以得出结论，FN1依赖性增强的CTC迁移需要通过ITGB1或SLUG的下游信号传导，并且ITGB1和SLUG的FN1调节可能对癌症进展和转移具有重要意义。
Fibronectin (FN1) is an extracellular matrix protein gaining increasing attention for its multifaceted roles in cancer progression. Using our recently established circulating tumor cell (CTC) lines, we had demonstrated increased FN1 expression and enhanced migration in CTC lines, in comparison to primary tumor cell lines. Whether increased FN1 expression is directly required for CTC migration, and the specific role of FN1's regulation of integrin B1 (ITGB1) and SLUG (SNAI2) in CTC migration remains unclear. Here, for the first time, we report that the knockdown of FN1, ITGB1, or SLUG expression in CTCs leads to a significant decrease in CTC migration. Knocking down two or all three of these proteins simultaneously did not further inhibit migration. We observed a corresponding increase in CTC migration when recombinant FN1 was added to CTCs. This effect was significantly impeded by prior knockdown of ITGB1 or SLUG. Using knock down experiments and western blotting analysis, we confirmed FN1's regulation of ITGB1 and SLUG to occur via two separate, independent pathways. Consequently, we can conclude that FN1-dependent enhanced migration of CTCs requires downstream signaling through either ITGB1 or SLUG and that FN1 regulation of ITGB1 and SLUG may have important implications for cancer progression and metastasis.