Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1α protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells

Xudong Tang, Qunzhou Zhang, Junko Nishitani, Jimmy Brown, Shihong Shi, Anh D. Le

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Abstract

Purpose: Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6- and E7-induced HIF-1α and VEGF gene expression. Experimental Design: Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1α small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1α/VEGF was measured using real-time PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6- and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1α/VEGF expression and in vitro angiogenesis was investigated. Results: HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1α protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1α siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6- and E7-induced HIF-1α and VEGF expression. Functionally, we showed that HPV-16 E6- and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1α siRNA or by treatment with resveratrol. Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1α-dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1α-mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.

Original languageEnglish (US)
Pages (from-to)2568-2576
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number9
DOIs
StatePublished - May 1 2007

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Hypoxia-Inducible Factor 1
Human papillomavirus 16
Oncogene Proteins
Vascular Endothelial Growth Factor A
Carcinoma
Uterine Cervical Neoplasms
Proteins
Small Interfering RNA
Cell Hypoxia
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Real-Time Polymerase Chain Reaction
Research Design
Western Blotting
Enzyme-Linked Immunosorbent Assay
resveratrol

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1α protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells. / Tang, Xudong; Zhang, Qunzhou; Nishitani, Junko; Brown, Jimmy; Shi, Shihong; Le, Anh D.

In: Clinical Cancer Research, Vol. 13, No. 9, 01.05.2007, p. 2568-2576.

Research output: Contribution to journalArticle

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title = "Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1α protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells",
abstract = "Purpose: Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6- and E7-induced HIF-1α and VEGF gene expression. Experimental Design: Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1α small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1α/VEGF was measured using real-time PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6- and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1α/VEGF expression and in vitro angiogenesis was investigated. Results: HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1α protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1α siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6- and E7-induced HIF-1α and VEGF expression. Functionally, we showed that HPV-16 E6- and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1α siRNA or by treatment with resveratrol. Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1α-dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1α-mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.",
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T1 - Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1α protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells

AU - Tang, Xudong

AU - Zhang, Qunzhou

AU - Nishitani, Junko

AU - Brown, Jimmy

AU - Shi, Shihong

AU - Le, Anh D.

PY - 2007/5/1

Y1 - 2007/5/1

N2 - Purpose: Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6- and E7-induced HIF-1α and VEGF gene expression. Experimental Design: Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1α small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1α/VEGF was measured using real-time PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6- and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1α/VEGF expression and in vitro angiogenesis was investigated. Results: HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1α protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1α siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6- and E7-induced HIF-1α and VEGF expression. Functionally, we showed that HPV-16 E6- and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1α siRNA or by treatment with resveratrol. Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1α-dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1α-mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.

AB - Purpose: Human papillomavirus (HPV)-16 oncoproteins, E6 and E7, are associated with enhanced tumor angiogenesis in human cervical cancers. The purpose of this study was (a) to investigate whether expression of HPV-16 E6 and E7 oncoproteins induces hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor expression in cervical cancer cells; and (b) to assess the effect of resveratrol on 16 E6- and E7-induced HIF-1α and VEGF gene expression. Experimental Design: Human cervical cancer cell lines C-33A and HeLa were transiently cotransfected with pSG5-HPV-16 E6 or 16 E7 constructs along with HIF-1α small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1α/VEGF was measured using real-time PCR, Western blot analysis, or ELISA. The in vitro angiogenic activity induced by 16 E6- and E7-transfected cells was examined. The effect of resveratrol on oncoprotein-induced HIF-1α/VEGF expression and in vitro angiogenesis was investigated. Results: HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1α protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1α siRNA or treatment with resveratrol. Blocking extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphoinositide-3-kinase by PD98059 and LY294002, respectively, abolished 16 E6- and E7-induced HIF-1α and VEGF expression. Functionally, we showed that HPV-16 E6- and E7-transfected cervical cancer cells stimulated in vitro capillary or tubule formation, and these angiogenic effects could be abolished either by cotransfection with HIF-1α siRNA or by treatment with resveratrol. Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1α-dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1α-mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.

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