Hypoxia induces actin cytoskeleton remodeling by regulating the binding of CAPZA1 to F-actin via PIP2 to drive EMT in hepatocellular carcinoma
Hypoxia induces actin cytoskeleton remodeling by regulating the binding of CAPZA1 to F-actin via PIP2 to drive EMT in hepatocellular carcinoma
复制标题
缺氧通过 PIP2 调节 CAPZA1 与 F-肌动蛋白的结合诱导肌动蛋白细胞骨架重塑，驱动肝细胞癌中的 EMT
DOI：
10.1016/j.canlet.2019.01.042
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Zheng, Shu-guo
中科院分区：
文献类型：
--
作者：
Huang, Deng;Cao, Li;Zheng, Shu-guo
研究表明，缺氧可通过缺氧诱导因子1α（HIF-1α）激活RhoA/ROCK信号通路，诱导细胞骨架损伤和重塑。我们前期的研究证实CAPZA1可以通过调节肌动蛋白细胞骨架重塑来调节EMT。然而，HIF-1α和CAPZA1之间的关系尚未阐明。因此，本研究旨在探讨缺氧通过调节肝细胞癌（HCC）细胞中CAPZA1诱导肌动蛋白细胞骨架重塑的机制。在本研究中，我们发现CAPZA1的低表达通过调节肌动蛋白细胞骨架重塑来驱动EMT，从而在体外和体内促进HCC细胞的侵袭和迁移。此外，我们发现PIP2和CAPZA1的结合使得CAPZA1能够从F-肌动蛋白的有刺末端释放，进而驱动肌动蛋白细胞骨架的重塑。最后，我们证实缺氧会增加 HCC 细胞中 PIP2 的水平及其通过 HIF-1 α/RhoA/ROCK1 途径与 CAPZA1 的结合。因此，CAPZA1和PIP2可以作为抑制HCC细胞缺氧促进的侵袭和迁移的治疗靶点。
Studies have shown that hypoxia can induce cytoskeletal injury and remodeling through the activation of the RhoA/ROCK signaling pathway by hypoxia-inducible factor-1 alpha (HIF-1 alpha). Our previous study confirmed that CAPZA1 can modulate EMT by regulating actin cytoskeleton remodeling. However, the relationship between HIF-1 alpha and CAPZA1 has not been illustrated. Therefore, this study aimed to investigate the mechanism by which hypoxia induces the remodeling of the actin cytoskeleton by regulating CAPZA1 in hepatocellular carcinoma (HCC) cells. In the present study, we showed that the low expression of CAPZA1 promotes HCC cell invasion and migration in vitro and in vivo by regulating actin cytoskeleton remodeling to drive EMT. Furthermore, we found that the combination of PIP2 and CAPZA1 enables CAPZA1 to be released from the barbed end of F-actin, which in turn drives the remodeling of the actin cytoskeleton. Finally, we confirmed that hypoxia increases PIP2 levels and its binding to CAPZA1 in HCC cells via the HIF-1 alpha/RhoA/ROCK1 pathway. Thus, CAPZA1 and PIP2 could be therapeutic targets to inhibit the invasion and migration promoted by hypoxia in HCC cells.