Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China; General Surgery Center, Chengdu Military General Hospital, Chengdu, Sichuan Province, 610083, China.
Cancer Lett. 2019 Apr 28;448:117-127. doi: 10.1016/j.canlet.2019.01.042. Epub 2019 Feb 8.
Studies have shown that hypoxia can induce cytoskeletal injury and remodeling through the activation of the RhoA/ROCK signaling pathway by hypoxia-inducible factor-1α (HIF-1α). Our previous study confirmed that CAPZA1 can modulate EMT by regulating actin cytoskeleton remodeling. However, the relationship between HIF-1α 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-1α/RhoA/ROCK1 pathway. Thus, CAPZA1 and PIP2 could be therapeutic targets to inhibit the invasion and migration promoted by hypoxia in HCC cells.
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。我们之前的研究证实 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 CAPZA1 诱导肝癌（HCC）细胞肌动蛋白细胞骨架重塑的机制。在本研究中，我们表明 CAPZA1 的低表达通过调节肌动蛋白细胞骨架重塑来驱动 EMT，从而促进 HCC 细胞在体外和体内的侵袭和迁移。此外，我们发现 PIP2 和 CAPZA1 的结合使 CAPZA1 从 F-肌动蛋白的突刺端释放，从而驱动肌动蛋白细胞骨架的重塑。最后，我们证实缺氧通过 HIF-1α/RhoA/ROCK1 通路增加 HCC 细胞中 PIP2 的水平及其与 CAPZA1 的结合。因此，CAPZA1 和 PIP2 可能成为治疗靶点，以抑制 HCC 细胞中缺氧促进的侵袭和迁移。
