Hypoxia promotes the expression of Von Willebrand factor in breast cancer cells by up-regulating the transcription factor YY1 and down-regulating the hsa-miR-424

Von Willebrand factor (VWF), a large glycoprotein with hemostatic properties, is mainly synthesized by megakaryocytes and endothelial cells (ECs). In recent years, studies have found that tumor cells also can produce VWF de novo. Tumor growth is usually accompanied by hypoxic environment, and whether hypoxia will influ-ence von Willebrand factor production in tumor cells is still unknown. In this research, we demonstrated that hypoxia could induce the production of VWF in breast cancer cells (MCF-7 and MDA-MB-231 cell lines), and promoted cell migration as well as angiogenesis. Notably, VWF is a key factor for hypoxia to promote breast cancer cell migration and angiogenesis, and knocking down VWF can attenuate the effects of hypoxia. Further study was conducted on the molecular mechanism to clarify why hypoxia can promote VWF synthesis in breast cancer cells. We found that Yin-Yang 1 (YY1, a transcription factor) had a binding site to the promoter region of VWF, and acted as a transcriptional activator of VWF. Meanwhile, hsa-miR-424 inhibited VWF production by associating with the 3 '-UTR of VWF mRNA. Here, we proved that hypoxia up-regulated the transcription factor YY1 and down-regulated hsa-miR-424 to increase the expression level of VWF. Additionally, knockdown of transcription factor YY1 and transfection of hsa-miR-424 mimics had a synergistic effect in reducing hypoxia-induced VWF production of breast cancer cells, cell migration and angiogenesis in vitro.