HIF-1α and HIF-2α have divergent roles in colon cancer

Hypoxia-inducible factor (HIF)-1 and HIF-2 are heterodimeric transcription factors that mediate the cellular response to hypoxia. Their key regulatory subunits, HIF-1 alpha and HIF-2 alpha are induced similarly by hypoxia, but their functional roles in cancer ill be distinct and isoform-specific. SW480 colon cancer cells with stable expression of siRNA to HIF-1 alpha or HIF-2 alpha or both were established. HIF-1 alpha-deficient cells displayed lower rates of proliferation and migration. but HIF-2 alpha-deficient cells exhibited enhanced anchorage independent growth in a soft agar assay. Xenograft studies revealed that HIF-1 alpha deficiency inhibited overall tumor growth. whereas deficiency of HIF-2 alpha stimulated tumor growth. In human colon cancer tissues, expression of HIF-1 alpha and to a lesser extent. HIF-2 alpha. was linked to upregulation of VEGF and tumor angiogenesis. However. loss of expression of HIF-2 alpha but not HIF-1 alpha was strongly correlated with advanced tumor stage. DNA microarray analysis identified distinct sets of HIF-1 alpha and HIF-2 alpha target genes that may explain these phenotypic differences. Collectively, these findings suggest that HIF isoforms may have differing cellular functions in colon cancer. In particular. HIF-1 alpha promoted the growth of SW480 colon cancer cells but HIF-2 alpha appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform-specific properties. (c) 2008 Wiley-Liss. Inc.