Abstract
The N-myc downstream-regulated gene 2 (NDRG2) is involved in tumor cell differentiation and apoptosis, but its function in tumor angiogenesis remains to be established. Here, we employed adenovirus overexpressing NDRG2 (Ad-NDRG2) to efficiently up-regulate target gene expression in the NDRG2-low-expressing, breast cancer cell line MCF-7. Moreover, VEGF secretion was decreased in MCF-7 cells infected by Ad-NDRG2, and medium conditioned by these infected cells could significantly inhibit the proliferation, tube formation and invasion of human umbilical vein endothelial cells (HUVECs). Further study indicated that the angiogenesis promoting factors VEGF and HIF-1α were down-regulated, whereas the angiogenesis suppressing factors p53 and VHL were up-regulated in MCF-7 cells infected by Ad-NDRG2. Finally, in a nude mouse model, intratumoral injections of Ad-NDRG2 every 3 days for 20 days significantly inhibited the growth and angiogenesis of xenografted MCF-7 tumors. In summary, these data indicate that NDRG2 may be involved in angiogenesis by impacting the expression of angiogenesis related factors. Thus, specific overexpression of NDRG2 by adenovirus represents a promising approach for the treatment of tumor angiogenesis.
Highlights
Breast cancer neovascularization (BCN), involving both angiogenesis and vasculogenesis, is a key event in tumorigenesis, invasion and metastasis
N-myc downstream-regulated gene 2 (NDRG2) expression in seven breast cancer cell lines was investigated by western blot and RT-PCR
The results showed that hypoxia-inducible factor (HIF)-1a expression was decreased in AdNDRG2-MCF-7 cells, and this was in accordance with the decreased vascular endothelial growth factor (VEGF) secretion
Summary
Breast cancer neovascularization (BCN), involving both angiogenesis and vasculogenesis, is a key event in tumorigenesis, invasion and metastasis. Hypoxia regulates many transcription factors, including hypoxia-inducible factor (HIF)-1a, which controls hypoxia-induced angiogenic factors such as vascular endothelial growth factor (VEGF) [2]. VEGF functions as a survival factor in endothelial cells and tumor cells via VEGF receptors that are up-regulated by hypoxia [3]. Increased VEGF expression by hypoxia, and thereby promotion of angiogenesis, may be a prerequisite for progressive growth and metastasis of solid tumors, such as breast cancer. VEGF expression is negatively regulated by p53 and VHL and is frequently overexpressed along with HIF-1a in human cancers [4,7]. To understand the interactions between angiogenesis promoting factors and angiogenesis suppressing factors, it is necessary to develop treatment strategies that specially target BCN
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