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Antioxid Redox Signal. 2010 Apr 15;12(8):933-43. doi: 10.1089/ars.2009.2917.

Nox-4-dependent nuclear H2O2 drives DNA oxidation resulting in 8-OHdG as urinary biomarker and hemangioendothelioma formation.

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Division of Plastic Surgery, Department of Surgery, Davis Heart Lung Research Institute, The Ohio State University, Columbus, Ohio 43212, USA.


Hemangioendotheliomas are classified as endothelial cell tumors, which are the most common soft tissue tumors in infants. In a murine model of hemangioendothelioma, we previously showed that MCP-1 is required for its development and that the expression of MCP-1 in EOMA cells is redox sensitive. Here, we sought to identify the source of oxidants that drive hemangioendothelioma formation. Seven known isoforms exist of the catalytic subunit gp91. Only the nox-4 isoform of gp91 was present in EOMA cells, in contrast with non-tumor-forming murine endothelial cells that contained multiple forms of nox. Nox-4 knockdown markedly attenuated MCP-1 expression and hemangioendothelioma formation. We report that in EOMA cells, nox-4 is localized such that it delivers H2O2 to the nuclear compartment. Such delivery of H2O2 causes oxidative modification of DNA, which can be detected in the urine of tumor-bearing mice as 8-hydroxy-2-deoxyguanosine. Iron chelation by in vivo administration of deferoxamine improved tumor outcomes. The current state of information connects nox-4 to MCP-1 to form a major axis of control that regulates the fate of hemangioendothelioma development in vivo.

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