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2017 ; 8
(35
): 58974-58984
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Dickkopf-1 induces angiogenesis via VEGF receptor 2 regulation independent of the
Wnt signaling pathway
#MMPMID28938611
Choi SH
; Kim H
; Lee HG
; Kim BK
; Park JY
; Kim DY
; Ahn SH
; Han KH
; Kim SU
Oncotarget
2017[Aug]; 8
(35
): 58974-58984
PMID28938611
show ga
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 ?-catenin or GSK3? 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.