Targeted replacement of hypoxia-inducible factor-1α by a hypoxia-inducible factor-2α knock-in allele promotes tumor growth

Hypoxia-inducible factors (HIF) are essential transcriptional regulators that mediate adaptation to hypoxic stress in rapidly growing tissues such as tumors. HIF activity is regulated by hypoxic stabilization of the related HIF-1 alpha and HIF-2 alpha-subunits, which are frequently overexpressed in cancer cells. To assess the relative tumor-promoting functions of HIF-1 alpha and HIF-2 alpha directly, we replaced HIF-1 alpha expression with HIF-2 alpha by creating a novel "knock-in" allele at the Hif-1 alpha locus through homologous recombination in primary murine embryonic stem cells. Compared with controls, s.c. teratomas derived from knock-in embryonic stem cells were larger and more proliferative, had increased microvessel density, and exhibited increased expression of vascular endothelial growth factor, transforming growth factor-alpha, and cyclin D1. These and other data indicate that HIF-2 alpha promotes tumor growth more effectively than HIF-1 alpha in multiple contexts.