Chien, Ming-HsienMing-HsienChienCHIA-CHI KUJohansson, GunnarGunnarJohanssonChen, Min-WeiMin-WeiChenHsiao, MichaelMichaelHsiaoSu, Jen-LiangJen-LiangSuInoue, HiroyasuHiroyasuInoueHua, Kuo-TaiKuo-TaiHuaLING-HUNG WEIKuo, Min-LiangMin-LiangKuo2022-02-252022-02-252009-121460-21800143-3334https://scholars.lib.ntu.edu.tw/handle/123456789/595796Vascular 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.enACUTE MYELOID-LEUKEMIA; CAMP-RESPONSE ELEMENT; CYCLOOXYGENASE-2 EXPRESSION; CANCER-CELLS; RECEPTOR VEGFR-3; VEGF-C/VEGFR-3 AXIS; TUMOR ANGIOGENESIS; LYMPHATIC VESSELS; FACTOR (VEGF)-C; JNK PATHWAYS[SDGs]SDG3journal article10.1093/carcin/bgp244198259682-s2.0-73949133917WOS:000272684700004https://scholars.lib.ntu.edu.tw/handle/123456789/458237