Abstract
This study explored the role of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in the production of ROS and tumor invasion. UCH-L1 was found to increase cellular ROS levels and promote cell invasion. Silencing UCH-L1, as well as inhibition of H2O2 generation by catalase or by DPI, a NOX inhibitor, suppressed the migration potential of B16F10 cells, indicating that UCH-L1 promotes cell migration by up-regulating H2O2 generation. Silencing NOX4, which generates H2O2, with siRNA eliminated the effect of UCH-L1 on cell migration. On the other hand, NOX4 overexpressed in HeLa cells happens to be ubiquitinated, and NOX4 following deubiquitination by UCH-L1, restored H2O2-generating activity. These in vitro findings are consistent with the results obtained in vivo with catalase (-/-) C57BL/6J mice. When H2O2 and UCH-L1 levels were independently varied in these animals, the former by infecting with H2O2-scavenging adenovirus-catalase, and the latter by overexpressing or silencing UCH-L1, pulmonary metastasis of B16F10 cells overexpressing UCH-L1 increased significantly in catalase (-/-) mice. In contrast, invasion did not increase when UCH-L1 was silenced in the B16F10 cells. These findings indicate that H2O2 levels regulated by UCH-L1 are necessary for cell invasion to occur and demonstrate that UCH-L1 promotes cell invasion by up-regulating H2O2 via deubiquitination of NOX4.
Highlights
Metastasis is the phenomenon in which tumor cells break away from a primary site, circulate through the bloodstream, infiltrate vascular and lymphatic vessels, and settle and proliferate elsewhere in the body [1,2,3]
B16F10 cells overexpressing ubiquitin C-terminal hydrolase-L1 (UCH-L1) showed increased ability for invasion, while knocking-down UCH-L1 decreased their invasiveness. These results suggest that there is a positive correlation between UCH-L1 expression levels and cell invasion
Pulmonary metastasis of UCH-L1-knocked-down B16F10 cells was significantly less than that of control cells in both catalase (-/-) and catalase (+/+) mice (Figure 2b and 2c). These results indicate that the effect of knocking down UCH-L1 on pulmonary metastasis of B16F10 cells is similar to that of infection with Adv-catalase, and that UCH-L1 is involved in H2O2–mediated cell invasion by altering H2O2 levels in invasive cells
Summary
Metastasis is the phenomenon in which tumor cells break away from a primary site, circulate through the bloodstream, infiltrate vascular and lymphatic vessels, and settle and proliferate elsewhere in the body [1,2,3]. This process involves the interplay of malignant cell- and host-associated factors [4], including the microenvironment of the extravasated cancer cells and factors that promote the survival and growth [5, 6] of the tumor cells. Inhibition of NOX4 suppressed the growth of melanoma cells, indicating that NOX4-generated ROS are required for transformation of melanoma cells [18]
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