Abstract
Angiogenesis is a crucial event during cancer progression that regulates tumor growth and metastasis. Activin receptor-like kinase 1 (ALK1), predominantly expressed in endothelial cells, plays a key role in the organization of neo-angiogenic vessels. Therapeutic targeting of ALK1 has been proposed as a promising strategy for cancer treatment, and microRNAs (miRNAs) are increasingly being explored as modulators of angiogenesis. However, the regulation of ALK1 by miRNAs is unclear. In this study, we identified that ALK1 is directly targeted by miR-199b-5p, which was able to inhibit angiogenesis in vitro and in vivo. Moreover, it was found that miR-199b-5p was repressed in breast cancer cells and its expression was decreased during the VEGF-induced angiogenesis process of human umbilical vein endothelial cells (HUVECs). Overexpression of miR-199b-5p inhibited the formation of capillary-like tubular structures and migration of HUVECs. Furthermore, overexpression of miR-199b-5p inhibited the mRNA and protein expression of ALK1 in HUVECs by directly binding to its 3’UTR. Additionally, overexpression of miR-199b-5p attenuated the induction of ALK1/Smad/Id1 pathway by BMP9 in HUVECs. Finally, overexpression of miR-199b-5p reduced tumor growth and angiogenesis in in vivo. Taken together, these findings demonstrate the anti-angiogenic role of miR-199b-5p, which directly targets ALK1, suggesting that miR-199b-5p might be a potential anti-angiogenic target for cancer therapy.
Highlights
Angiogenesis is a physiological process that is defined as the formation of new blood vessels from pre-existing vessels (Ramjiawan et al, 2017)
Since the in vitro experiments showed that miR-199b-5p inhibits the angiogenic activity and migration of human umbilical vein endothelial cells (HUVECs), we further investigated whether miR-199b-5p could inhibit tumor angiogenesis and growth in vivo
We identified for the first time that miR-199b-5p is a negative regulator of angiogenesis in HUVECs
Summary
Angiogenesis is a physiological process that is defined as the formation of new blood vessels from pre-existing vessels (Ramjiawan et al, 2017). The process of angiogenesis is crucial for normal processes such as wound healing, tissue growth and regeneration, and placental development, and for pathophysiological changes such as cancer progression (Petrovic, 2016). Several pro-angiogenic factors such as vascular endothelial growth factor (VEGF), vascular endothelial factor (TGF), and interleukin-8 (IL-8) increase the motility, proliferation, and survival of endothelial cells (He et al, 2014). Angiogenesis inhibitors such as angiostatin, endostatin, and interferons can promote tumor starvation and trigger cell death (Lin et al, 2016)
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