title: Vascular endothelial growth factor-C (VEGF-C) promotes angiogenesis by induction of COX-2 in leukemic cells via the VEGF-R3/JNK/AP-1 pathway.
abstract: Vascular endothelial growth factor (VEGF)-C is recognized as a tumor lymphangiogenic factor based on the effects of activated VEGF-R3 on lymphatic endothelial cells. Many tumor cells express VEGF-R3 but the function of this receptor in tumor cells is largely unknown. It has been reported that the VEGF-C/VEGF-R3 axis is activated in subsets of leukemia patients. Herein, we have shown that VEGF-C induces angiogenic activity in the tube formation assay invitro and Matrigel plug assay in vivo by upregulating an angiogenic factor, cyclooxygenase-2 (COX-2), through VEGF-R3 in the human acute myeloid leukemia (AML) cell line, THP-1. COX-2 induction by VEGF-C was also observed in other VEGF-R3(+) human AML cell lines (U937 and HL60). Moreover, immunohistochemical analysis of bone marrow specimens of 37 patients diagnosed with AML revealed that VEGF-C expression in specimens was associated with the expression of COX-2 (P < 0.001). The manner by which signaling pathways transduced by VEGF-C is responsible for COX-2 upregulation was further investigated. Blocking the p42/44 mitogen-activated protein kinase (MAPK) pathway with the MAPK kinase inhibitor, PD 98059, failed to inhibit VEGF-C-mediated COX-2 expression. However, VEGF-C-induced COX-2 upregulation was effectively abolished by overexpression of dominant-negative c-Jun N-terminal kinase (JNK) or treatment with the JNK inhibitor, SP 600125. VEGF-C induced JNK-dependent nuclear translocation of c-Jun. Furthermore, chromatin immunoprecipitation and reporter assays revealed that VEGF-C enhanced c-Jun binding to the cyclic adenosine 3',5'-monophosphate-response element of the COX-2 promoter and induced COX-2 expression. In sum, the data herein highlight the pathogenic role of VEGF-C in leukemia via regulation of angiogenesis through upregulation of COX-2.
authors.affiliation: Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine and Angiogenesis Research Center, National Taiwan University, No. 1, Sec. 1, Ren-Ai Road, Taipei 10016, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Ku
authors.forename: Gunnar
authors.initials: G
authors.lastname: Johansson
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Inoue
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.forename: Lin-Hung
authors.initials: LH
authors.lastname: Wei
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
mesh_terms: D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009389:Neovascularization, Pathologic; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020298:U937 Cells; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D018808:Transcription Factor AP-1; D042582:Vascular Endothelial Growth Factor C; D051546:Cyclooxygenase 2; D040321:Vascular Endothelial Growth Factor Receptor-3; D048670:MAP Kinase Kinase 4