HIF-1alpha and HIF-2alpha 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-1alpha and HIF-2alpha, 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-1alpha or HIF-2alpha or both were established. HIF-1alpha-deficient cells displayed lower rates of proliferation and migration, but HIF-2alpha-deficient cells exhibited enhanced anchorage independent growth in a soft agar assay. Xenograft studies revealed that HIF-1alpha deficiency inhibited overall tumor growth, whereas deficiency of HIF-2alpha stimulated tumor growth. In human colon cancer tissues, expression of HIF-1alpha and to a lesser extent, HIF-2alpha, was linked to upregulation of VEGF and tumor angiogenesis. However, loss of expression of HIF-2alpha but not HIF-1alpha was strongly correlated with advanced tumor stage. DNA microarray analysis identified distinct sets of HIF-1alpha and HIF-2alpha 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-1alpha promoted the growth of SW480 colon cancer cells but HIF-2alpha appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform-specific properties.
Imamura
Takaaki
T
Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Kikuchi
Hirotoshi
H
Herraiz
Maria-Teresa
MT
Park
Do-Youn
DY
Mizukami
Yusuke
Y
Mino-Kenduson
Mari
M
Lynch
Maureen P
MP
Rueda
Bo R
BR
Benita
Yair
Y
Xavier
Ramnik J
RJ
Chung
Daniel C
DC
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse