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Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner

Oncogene volume 19, pages 4611–4620 (2000)Cite this article

Abstract

Like other types of pre-malignant lesions and carcinoma, angiogenesis is associated with high-grade cervical dysplasia and with invasive squamous carcinoma of the cervix. Vascular endothelial cell growth factor (VEGF) is known to be one of the most important inducers of angiogenesis and is upregulated in carcinoma of the cervix. Human Papilloma Virus 16 (HPV-16) has been etiologically linked to human cervical cancer, and the major oncogenic proteins encoded by the viral genome, E6 and E7, are involved in the immortalization of target cells. Because several oncogenes including mutant ras, EGF receptor, ErbB2/Her2, c-myc and v-src upregulate VEGF expression, we asked whether HVP-16 E6 oncoprotein could act in a similar fashion. We found that HPV-16 E6-positive cells generally express high levels of VEGF message. Furthermore, co-expression of the VEGF promoter-Luc (luciferase) reporter gene with E6 in both human keratinocytes and mouse fibroblast showed that E6 oncoprotein upregulates VEGF promoter activity, and does so in a p53 independent manner. An E6 responsive region which comprises four Sp-1 sites, between −194 and −50 bp of the VEGF promoter, is also necessary for constitutive VEGF transcription. Taken together, our results suggest the possibility that the HPV oncoprotein E6 may contribute to tumor angiogenesis by direct stimulation of the VEGF gene.

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Acknowledgements

We are grateful to Dr Lawrence Banks for providing J4Ω16E6 and PJ4Ω plasmids. We gratefully thank Dr Larry Donehower and Dr Yaacov Ben-David for help in providing MEF p53+/+ and p53−/− cells. Dr Federico DeMarco's help in providing HPK1A cells is also highly appreciated. Ms Lynda Woodcock and Mrs Cassandra Cheng provided excellent secretarial assistance. This work was supported by grants from the Medical Research Council of Canada (MT-5815) and National Institutes of Health, USA (CA-41233) to RS Kerbel.

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  1. Omar López-Ocejo and Alicia Viloria-Petit: Omar López-Ocejo and A Viloria-Petit contributed equally

Authors and Affiliations

  1. Vaccine Division, Centre for Genetic Engineering and Biotechnology, PO Box 6162, C Havana, 10600, Cuba

    Omar López-Ocejo

  2. Pharmaceutical Division, Centre for Genetic Engineering and Biotechnology, PO Box 6162, C Havana, 10600, Cuba

    Mónica Bequet-Romero

  3. Division of Cancer Biology Research, Sunnybrook and Women's College Health Sciences Centre, S-218, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada

    Alicia Viloria-Petit & Robert S Kerbel

  4. Department of Medical Biophysics, Division of Cancer Biology Research, University of Toronto, Sunnybrook and Women's College Health Sciences Centre, S-218, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada

    Robert S Kerbel

  5. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02215, Massachusetts, MA, USA

    Debabrata Mukhopadhyay

  6. Hamilton Civic Hospitals Research Centre, McMaster University, 711 Concession Street, Hamilton, L8W 1C3, Ontario, Canada

    Janusz Rak

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López-Ocejo, O., Viloria-Petit, A., Bequet-Romero, M. et al. Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner. Oncogene 19, 4611–4620 (2000). https://doi.org/10.1038/sj.onc.1203817

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