Abstract
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.
Highlights
IntroductionDKK-1 acts as an inhibitory ligand of the low-density lipoprotein receptor-related protein 5/6 co-receptors and subsequently blocks their interaction with Wnt, resulting in β-catenin degradation [2]
Dickkopf-1 (DKK-1) is a potent antagonist of Wnt/ β-catenin signaling [1]
Tung et al reported that a DKK-1expressing hepatocellular carcinoma (HCC) cell line showed an increased microvessel density around tumors [13], while another study showed that DKK-1–mediated endothelial cell activation led to increased vascular density and vessel diameter in rats [14]
Summary
DKK-1 acts as an inhibitory ligand of the low-density lipoprotein receptor-related protein 5/6 co-receptors and subsequently blocks their interaction with Wnt, resulting in β-catenin degradation [2] This inhibitory role of DKK-1 in Wnt/β-catenin signaling is supported by the downregulation of DKK-1 in human colon cancers and the correlation between high DKK-1 expression and favorable responses to chemotherapy in brain tumors [3]. Tung et al reported that a DKK-1expressing HCC cell line showed an increased microvessel density around tumors [13], while another study showed that DKK-1–mediated endothelial cell activation led to increased vascular density and vessel diameter in rats [14] These findings indicate that DKK-1 plays a role in microvascular remodeling and tumor angiogenesis activation, which may account for its promotion of cancer growth in vivo
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