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

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...

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Bibliographic Details
Published in:Clinical cancer research 2007-05, Vol.13 (9), p.2568-2576
Main Authors: XUDONG TANG, QUNZHOU ZHANG, NISHITANI, Junko, BROWN, Jimmy, SHIHONG SHI, LE, Anh D
Format: Article
Language:English
Subjects:
angiogenesis
Angiogenic factors and receptors
Anticarcinogenic Agents - pharmacology
Antineoplastic agents
Biological and medical sciences
Carcinoma - genetics
Carcinoma - metabolism
Cellular, Molecular, and Tumor Biology
Chromones - pharmacology
DNA tumor viruses
Female
Female genital diseases
Flavonoids - pharmacology
Gynecologic cancers: cervical
Gynecology. Andrology. Obstetrics
HeLa Cells
HIF-1α
HPV oncoprotein
human cervical cancer
Human papillomavirus 16
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - analysis
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Medical sciences
Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors
Morpholines - pharmacology
Neovascularization, Pathologic - genetics
Neovascularization, Pathologic - metabolism
Oncogene Proteins, Viral - genetics
Papillomavirus E7 Proteins
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Repressor Proteins - genetics
RNA, Small Interfering - genetics
RNA, Small Interfering - pharmacology
Stilbenes - pharmacology
Transcriptional Activation
Transfection
Tumors
Uterine Cervical Neoplasms - genetics
Uterine Cervical Neoplasms - metabolism
Vascular Endothelial Growth Factor A
VEGF
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Summary: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 (ERK 1/2) 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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-06-2704