Angiogenesis plays a pivotal role in tumor growth. The hypoxia-inducible factor 1, alpha subunit (HIF-1 alpha)/vascular endothelial growth factor pathway is the most important pathway for regulating angiogenesis in the tumor microenvironment. c-Myc is an important oncogene that has many biological functions. In this study, we investigated the role of c-Myc in tumor angiogenesis. We found that the overexpression of c-Myc in colon cancer cells could promote the expression of HIF-1 alpha and that of vascular endothelial growth factor. Moreover, we found that c-Myc regulated HIF-1 alpha at the post-transcriptional level. The results revealed c-Myc-dependent regulation of HIF-1 alpha instead of HIF-1 alpha-dependent c-Myc regulation for the first time. They also showed that c-Myc was essential to regulate colon cancer cell-mediated angiogenesis and contributed to tumor growth. This research provides the theoretical basis for clinical trials of new therapeutic targets of c-Myc and HIF-1 alpha in colon cancer cells. (C) 2012 Elsevier Inc. All rights reserved.