HIF-1α and HIF-2α have divergent roles in colon cancer
Article first published online: 30 SEP 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 124, Issue 4, pages 763–771, 15 February 2009
How to Cite
Imamura, T., Kikuchi, H., Herraiz, M.-T., Park, D.-Y., Mizukami, Y., Mino-Kenduson, M., Lynch, M. P., Rueda, B. R., Benita, Y., Xavier, R. J. and Chung, D. C. (2009), HIF-1α and HIF-2α have divergent roles in colon cancer. Int. J. Cancer, 124: 763–771. doi: 10.1002/ijc.24032
- Issue published online: 11 DEC 2008
- Article first published online: 30 SEP 2008
- Accepted manuscript online: 30 SEP 2008 12:00AM EST
- Manuscript Accepted: 16 SEP 2008
- Manuscript Received: 11 APR 2008
- NIH. Grant Number: CA92594
- Kate J. and Dorothy L. Clapp Fund
- 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-1α and HIF-2α, are induced similarly by hypoxia, but their functional roles in cancer may be distinct and isoform-specific. SW480 colon cancer cells with stable expression of siRNA to HIF-1α or HIF-2α or both were established. HIF-1α-deficient cells displayed lower rates of proliferation and migration, but HIF-2α-deficient cells exhibited enhanced anchorage independent growth in a soft agar assay. Xenograft studies revealed that HIF-1α deficiency inhibited overall tumor growth, whereas deficiency of HIF-2α stimulated tumor growth. In human colon cancer tissues, expression of HIF-1α and to a lesser extent, HIF-2α, was linked to upregulation of VEGF and tumor angiogenesis. However, loss of expression of HIF-2α but not HIF-1α was strongly correlated with advanced tumor stage. DNA microarray analysis identified distinct sets of HIF-1α and HIF-2α 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-1α promoted the growth of SW480 colon cancer cells but HIF-2α appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform-specific properties. © 2008 Wiley-Liss, Inc.