title: Nox-4-dependent nuclear H2O2 drives DNA oxidation resulting in 8-OHdG as urinary biomarker and hemangioendothelioma formation.
abstract: 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.
authors.affiliation: Division of Plastic Surgery, Department of Surgery, Davis Heart Lung Research Institute, The Ohio State University, Columbus, Ohio 43212, USA. gayle.gordillo@osumc.edu
authors.forename: Gayle
authors.initials: G
authors.lastname: Gordillo
authors.forename: Huiqing
authors.initials: H
authors.lastname: Fang
authors.forename: Hana
authors.initials: H
authors.lastname: Park
authors.forename: Sashwati
authors.initials: S
authors.lastname: Roy
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015415:Biomarkers / Q000652:urine; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000652:urine; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D006390:Hemangioendothelioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016877:Oxidants; D034741:RNA, Small Interfering; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D003849:Deoxyguanosine