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Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors

Oncogene volume 23, pages 2988–2995 (2004)Cite this article

Abstract

Human papillomavirus (HPV) 16 is involved in causing cervical cancer. The E6 and E7 proteins of HPV 16 immortalize human keratinocytes and this is due, at least in part, to inactivation of the tumor suppressor proteins p53 and pRB. These tumor suppressor proteins also regulate the expression of pro- and antiangiogenic factors by cells. For this reason, experiments were conducted to determine whether the expression of E6 and E7 in primary keratinocytes alters the phenotype of these cells such that they express diminished levels of antiangiogenic factors and/or increased levels of proangiogenic factors. To avoid variances in experimental observations, pools of human foreskin keratinocytes from multiple sources were infected with recombinant retrovirus expressing HPV 16 E6 and E7 or control retrovirus. Gene array analysis, RT–PCR, ELISAs and Western blotting showed that in cells expressing HPV 16 E6 and E7, expression levels of two potent angiogenesis inhibitors, thrombospondin-1 and maspin, were lower compared to controls. Additionally, major angiogenesis inducers, interleukin-8 and vascular endothelial growth factor (VEGF), were increased relative to controls. VEGF can be produced as multiple splice variants, all of which are required for the formation of patent blood vessels. The expression of HPV 16 E6 and E7 in keratinocytes augmented expression of VEGF 121, 145, 165 and 189. These observations show that HPV 16 E6 and E7 alter the phenotype of primary keratinocytes, diminishing expression of inhibitors and increasing expression of inducers of angiogenesis. This altered phenotype may permit keratinocytes infected by HPV 16 to play a role in the progression of cancer by permitting tumors to acquire a blood supply permissive of growth and spread.

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Acknowledgements

We thank Noel Bouck, Lindsey Mayo, Shiv Srivastava and Olga Volpert for reagents and helpful discussion, Jean Bang and Grova Mae Lewis for excellent technical assistance and Denise Galloway for providing the retroviral packaging cell lines. This work was supported by NIH Grant AI31494 and INGEN (to AR), NIH Grants CA73023 and CA67891 (to DBD) and an NIH Predoctoral Minority Research Supplement (to ETS). The Indiana Genomics Initiative (INGEN) of Indiana University is supported in part by Lilly Endowment Inc.

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  1. Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine and Walther Cancer Institute, 46202-5120, IN, USA

    Esra Toussaint-Smith, David B Donner & Ann Roman

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  1. Esra Toussaint-Smith
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Correspondence to Ann Roman.

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Toussaint-Smith, E., Donner, D. & Roman, A. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene 23, 2988–2995 (2004). https://doi.org/10.1038/sj.onc.1207442

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