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Overexpression of Human Papillomavirus Type 16 Oncoproteins Enhances Hypoxia-Inducible Factor 1 Protein Accumulation and Vascular Endothelial Growth Factor Expression in Human Cervical Carcinoma Cells

Authors' Affiliations: ¹ Center for Craniofacial Molecular Biology, University of Southern California, School of Dentistry and ² Department of Otolaryngology, Charles R. Drew University of Medicine and Science, Los Angeles, California

Requests for reprints: Anh D. Le, Division of Surgical, Therapeutic and Bioengineering Sciences, Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Health Sciences Campus, 2250 Alcazar Street, CSA103, Los Angeles, CA 90033. Phone: 323-442-2556; Fax: 323-442-2981; E-mail: anhle{at}usc.edu.

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 1 (HIF-1) 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-1 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-1 small interfering RNA (siRNA) or nonspecific siRNA. The expression of HIF-1/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-1/VEGF expression and in vitro angiogenesis was investigated.

Results: HPV-16 E6- and E7-transfected cervical cancer cells express increased HIF-1 protein and VEGF expression. These stimulatory effects were abrogated by cotransfection with either HIF-1 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-1 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-1 siRNA or by treatment with resveratrol.

Conclusion: HPV-16 oncoproteins contribute to enhanced angiogenesis in cervical cancer cells via HIF-1–dependent VEGF expression. Resveratrol suppresses 16 E6- and E7-induced HIF-1–mediated angiogenic activity and, thus, is a promising chemotherapeutic agent for human cervical cancer.