The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression |
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Institution: | 1. Department of Radiology, University of Iowa, Iowa City, IA;2. Department of Biomedical Engineering, University of Iowa, Iowa City, IA;3. Department of Psychiatry, University of Iowa, Iowa City, IA;4. Department of Veterans Affairs Medical Center, Iowa City, IA;1. Department of Nephrology, First People''s Hospital of Kunshan, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu 215300, China;2. Department of Pediatrics, First Hospital of Jilin University, Changchun 130031, China;3. Department of Pneumology, Second Hospital of Jilin University, Changchun 130041, China;4. Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;5. Department of Pediatrics, Peking University First Hospital, Beijing 100034, China |
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Abstract: | 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. |
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Keywords: | NOX4 NADPH oxidase Reactive oxygen species Hepatocyte proliferation Hepatocellular carcinoma Liver cancer Liver regeneration Hepatocarcinogenesis Free radicals |
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