Song In-Kang, Kim Hyun Jung, Magesh Venkataraman, Lee Kong-Joo
Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Graduate School of Pharmaceutical Sciences and College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Biochem Biophys Res Commun. 2018 Jan 1;495(1):1567-1572. doi: 10.1016/j.bbrc.2017.11.051. Epub 2017 Nov 8.
Ubiquitin C-terminal hydrolase-L1 (UCH-L1), which catalyzes the hydrolysis of ubiquitin esters and amides, is highly expressed in brain. Recently, UCH-L1 has been found to increase cancer cell migration and invasion by modulating hydrogen peroxide generated by NADPH oxidase 4 (NOX4). Because angiogenesis is also mediated by hydrogen peroxide, we explored the role of UCH-L1 in angiogenesis in human umbilical vein endothelial cells (HUVECs). Silencing UCH-L1 suppressed tubule formation in HUVECs, indicating that UCH-L1 promotes angiogenesis in vitro. This was confirmed using in vivo Matrigel plug studies of HUVECs, after overexpressing or silencing UCH-L1. Silencing UCH-L1 significantly suppressed VEGF-induced ROS levels as well as activation of VEGFR, both of which are required for angiogenesis. This study also showed that UCH-L1 promotes angiogenesis of HUVECs, as well as invasion in cancer cells, by up-regulating ROS by deubiquitination of NOX4, suggesting that UCH-L1 plays a key role in angiogenesis of HUVECS by regulating ROS levels by deubiquitination of NOX4.
泛素羧基末端水解酶-L1（UCH-L1）催化泛素酯和酰胺的水解，在大脑中高度表达。最近，人们发现UCH-L1通过调节NADPH氧化酶4（NOX4）产生的过氧化氢来增加癌细胞的迁移和侵袭。由于血管生成也由过氧化氢介导，我们探讨了UCH-L1在人脐静脉内皮细胞（HUVECs）血管生成中的作用。沉默UCH-L1可抑制HUVECs中的小管形成，表明UCH-L1在体外促进血管生成。在过表达或沉默UCH-L1后，使用HUVECs的体内基质胶栓研究证实了这一点。沉默UCH-L1可显著抑制VEGF诱导的ROS水平以及VEGFR的激活，而这两者都是血管生成所必需的。这项研究还表明，UCH-L1通过去泛素化NOX4上调ROS，从而促进HUVECs的血管生成以及癌细胞的侵袭，提示UCH-L1通过去泛素化NOX4调节ROS水平，在HUVECs的血管生成中起关键作用。
