Cancer Cell Biology
Treatment with siRNA and antisense oligonucleotides targeted to HIF-1α induced apoptosis in human tongue squamous cell carcinomas
Article first published online: 20 MAY 2004
Copyright © 2004 Wiley-Liss, Inc.
International Journal of Cancer
Volume 111, Issue 6, pages 849–857, 10 October 2004
How to Cite
Zhang, Q., Zhang, Z.-F., Rao, J. Y., Sato, J. D., Brown, J., Messadi, D. V. and Le, A. D. (2004), Treatment with siRNA and antisense oligonucleotides targeted to HIF-1α induced apoptosis in human tongue squamous cell carcinomas. Int. J. Cancer, 111: 849–857. doi: 10.1002/ijc.20334
- Issue published online: 3 AUG 2004
- Article first published online: 20 MAY 2004
- Manuscript Accepted: 11 MAR 2004
- Manuscript Received: 3 OCT 2003
- National Institute of Health. Grant Numbers: 1S11 AR47359, P20-RR16463
Overexpression of hypoxia inducible factor-1α (HIF-1α) in cancers has been correlated to a more aggressive tumor phenotype. We investigated the effect of HIF-1α knockout on the in vitro survival and death of human tongue squamous cell carcinomas (SCC-4 and SCC-9). Under normoxic condition, a basal level of HIF-1α protein was constitutively expressed in SCC-9 cells, albeit an undetectable level of HIF-1α messages. Exposure to hypoxia induced only a transient increase in mRNA transcript but a prolonged elevation of HIF-1α protein and its immediate downstream target gene product, VEGF. Under normoxic or hypoxic conditions, treatment of SCC-9 cells with AS-HIF-1α ODN suppressed both constitutive and hypoxia-induced HIF-1α expression at both mRNA and protein levels. Knockout of HIF-1α gene expression via either AS-HIF-1α ODN or siRNA (siRNAHIF-1α) treatment resulted in inhibition of cell proliferation and induced apoptosis in SCC-4 and SCC-9 cells. We also demonstrated that exposure of SCC-9 cells to hypoxia led to a time-dependent increase in the expression of bcl-2 and IAP-2, but not p53. The attenuated levels of bcl-2 and IAP-2, and the enhanced activity of caspase-3 after treatment with AS-HIF-1α ODN may contribute partly to the effects of HIF-1α blockade on SCC-9 cell death. Collectively, our data suggest that a constitutive or hypoxia-induced expression of HIF-1α in SCC-9 and SCC-4 cells is sufficient to confer target genes expression essential for tumor proliferation and survival. As a result, interfering with HIF-1α pathways by antisense or siRNA strategy may provide a therapeutic target for human tongue squamous cell carcinomas. © 2004 Wiley-Liss, Inc.