Treatment with siRNA and antisense oligonucleotides targeted to HIF-1α induced apoptosis in human tongue squamous cell carcinomas

Qunzhou Zhang, Zuo Feng Zhang, Jian Y. Rao, J. Denry Sato, Jimmy Brown, Diana V. Messadi, Anh D. Le

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)849-857
Number of pages9
JournalInternational Journal of Cancer
Volume111
Issue number6
DOIs
StatePublished - Oct 10 2004

Fingerprint

Hypoxia-Inducible Factor 1
Antisense Oligonucleotides
Tongue
Small Interfering RNA
Squamous Cell Carcinoma
Apoptosis
Gene Expression
Cell Hypoxia
Neoplasms
Messenger RNA
Proteins
Survival
Caspase 3
Vascular Endothelial Growth Factor A
Cell Death

Keywords

  • Antisense
  • Apoptosis
  • Bcl-2
  • HIF-1α
  • IAP-2
  • siRNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Treatment with siRNA and antisense oligonucleotides targeted to HIF-1α induced apoptosis in human tongue squamous cell carcinomas. / Zhang, Qunzhou; Zhang, Zuo Feng; Rao, Jian Y.; Sato, J. Denry; Brown, Jimmy; Messadi, Diana V.; Le, Anh D.

In: International Journal of Cancer, Vol. 111, No. 6, 10.10.2004, p. 849-857.

Research output: Contribution to journalArticle

Zhang, Qunzhou ; Zhang, Zuo Feng ; Rao, Jian Y. ; Sato, J. Denry ; Brown, Jimmy ; Messadi, Diana V. ; Le, Anh D. / Treatment with siRNA and antisense oligonucleotides targeted to HIF-1α induced apoptosis in human tongue squamous cell carcinomas. In: International Journal of Cancer. 2004 ; Vol. 111, No. 6. pp. 849-857.
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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.",
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AU - Zhang, Qunzhou

AU - Zhang, Zuo Feng

AU - Rao, Jian Y.

AU - Sato, J. Denry

AU - Brown, Jimmy

AU - Messadi, Diana V.

AU - Le, Anh D.

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AB - 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.

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