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Dickkopf-1 induces angiogenesis via VEGF receptor 2 regulation independent of the Wnt signaling pathway

 Sung Hoon Choi  ;  Hyemi Kim  ;  Hyun Gyu Lee  ;  Beom Kyung Kim  ;  Jun Yong Park  ;  Do Young Kim  ;  Sang Hoon Ahn  ;  Kwang-Hyub Han  ;  Seung Up Kim 
 ONCOTARGET , Vol.8(35) : 58974-58984, 2017 
Journal Title
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HUVEC ; Hepatocellular carcinoma ; angiogenesis ; dickkopf-1 ; vascular endothelial growth factor receptor
Tumor angiogenesis is essential for invasive tumor growth and metastasis. Dickkopf-1 (DKK-1), an antagonist of Wnt signaling, participates in tumor development and progression. We evaluated whether DKK-1 stimulation induces angiogenesis and the endothelial-mesenchymal transition (EnMT). Human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant DKK-1 (rDDK-1) or conditioned medium from a culture of DKK-1-transfected 293 cells. Following stimulation, the expression levels of angiogenesis-related factors and EnMT related markers were determined by immunoblot assays. In addition, the effects of exogenous DKK-1 on angiogenesis and EnMT were assessed by tube-formation, cell invasion, and wound-healing assays. Human hepatoma cells, such as Hep3B and Huh-7, showed high levels of DKK-1 expression, whereas 293 cells and HUVECs showed little or no DKK-1 expression. Increased endothelial cell tube formation and invasiveness were observed in HUVECs treated with concentrated conditioned medium from DKK-1-overexpressing 293 cells or rDKK-1. DKK-1-stimulated HUVECs also exhibited increased motility in wound-healing assays. Furthermore, the expression levels of angiogenesis-related factors, including vascular endothelial growth factor receptor 2 and vascular endothelial-cadherin, were increased in DKK-1-stimulated HUVECs. The expression of EnMT markers, such as vimentin and Twist, was also increased in DKK-1-stimulated HUVECs. However, no significant change in β-catenin or GSK3β expression was observed. Our in vitro data suggest that DKK-1 can enhance angiogenesis and EnMT by HUVECs independent of the Wnt signaling pathway. Modulation of DKK-1 expression may facilitate development of novel strategies to control tumor angiogenesis and metastasis.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영)
Kim, Beom Kyung(김범경) ORCID logo https://orcid.org/0000-0002-5363-2496
Kim, Seung Up(김승업) ORCID logo https://orcid.org/0000-0002-9658-8050
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
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