Treatment With siRNA and Antisense Oligonucleotides Targeted to HIF-1α Induced Apoptosis in Human Tongue Squamous Cell Carcinomas
Penn collection
Degree type
Discipline
Subject
Apoptosis
Bcl-2
HIF-1α
IAP-2
siRNA
Apoptosis
Carcinoma
Squamous Cell
Cell Hypoxia
Cell Survival
Humans
Hypoxia-Inducible Factor 1
alpha Subunit
Oligonucleotides
Antisense
Phenotype
RNA
Messenger
RNA
Small Interfering
Tongue Neoplasms
Transcription Factors
Tumor Cells
Cultured
antisense oligonucleotide
caspase 3
gene product
hypoxia inducible factor 1alpha
iap 2 protein
protein
protein bcl 2
protein p53
small interfering RNA
unclassified drug
apoptosis
article
cancer growth
cell death
cell proliferation
cell survival
controlled study
enzyme activity
gene expression
gene overexpression
gene targeting
human
human cell
hypoxia
in vitro study
knockout gene
phenotype
priority journal
protein expression
RNA transcription
squamous cell carcinoma
tongue carcinoma
Dentistry
Oral and Maxillofacial Surgery
Oral Biology and Oral Pathology
Periodontics and Periodontology
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Abstract
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-1αa expression at both mRNA and protein levels; Knockout of HIF-αa gene expression via either AS-HIF-1α ODN or siRNA (siRNA HIF-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.