The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression.
The NADPH oxidase NOX4 has emerged as an important source of reactive oxygen species in signal transduction, playing roles in physiological and pathological processes. NOX4 mediates transforming growth factor-β-induced intracellular signals that provoke liver fibrosis, and preclinical assays have suggested NOX4 inhibitors as useful tools to ameliorate this process. However, the potential consequences of sustained treatment of liver cells with NOX4 inhibitors are yet unknown. The aim of this work was to analyze whether NOX4 plays a role in regulating liver cell growth either under physiological conditions or during tumorigenesis. In vitro assays proved that stable knockdown of NOX4 expression in human liver tumor cells increased cell proliferation, which correlated with a higher percentage of cells in S/G2/M phases of the cell cycle, downregulation of p21(CIP1/WAF1), increase in cyclin D1 protein levels, and nuclear localization of β-catenin. Silencing of NOX4 in untransformed human and mouse hepatocytes also increased their in vitro proliferative capacity. In vivo analysis in mice revealed that NOX4 expression was downregulated under physiological proliferative situations of the liver, such as regeneration after partial hepatectomy, as well as during pathological proliferative conditions, such as diethylnitrosamine-induced hepatocarcinogenesis. Xenograft experiments in athymic mice indicated that NOX4 silencing conferred an advantage to human hepatocarcinoma cells, resulting in earlier onset of tumor formation and increase in tumor size. Interestingly, immunochemical analyses of NOX4 expression in human liver tumor cell lines and tissues revealed decreased NOX4 protein levels in liver tumorigenesis. Overall, results described here strongly suggest that NOX4 would play a growth-inhibitory role in liver cells.
['Crosas-Molist|Eva|E|', 'Bertran|Esther|E|', 'Sancho|Patricia|P|', 'López-Luque|Judit|J|', 'Fernando|Joan|J|', 'Sánchez|Aránzazu|A|', 'Fernández|Margarita|M|', 'Navarro|Estanis|E|', 'Fabregat|Isabel|I|']
D000818:Animals D017209:Apoptosis D063646:Carcinogenesis D045744:Cell Line, Tumor D049109:Cell Proliferation D019938:Cyclin D1 D015972:Gene Expression Regulation, Neoplastic D022781:Hepatocytes D006801:Humans D008113:Liver Neoplasms D051379:Mice D000074663:NADPH Oxidase 4 D019255:NADPH Oxidases D017382:Reactive Oxygen Species D015398:Signal Transduction D016212:Transforming Growth Factor beta D023041:Xenograft Model Antitumor Assays
NADPH oxidase NOX4 Hepatocyte proliferation Liver cancer Reactive oxygen species Hepatocarcinogenesis Free radicals Hepatocellular carcinoma Liver regeneration