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The cellular transcription factor Brn-3a and the smoking-related substance nicotine interact to regulate the activity of the HPV URR in the cervix

Oncogene volume 29, pages 2701–2711 (2010)Cite this article

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Abstract

The cellular transcription factor Brn-3a differentially regulates different human papilloma virus (HPV)-16 variants that are associated with different risks of progression to cervical carcinoma in infected humans. The upstream regulatory regions (URRs) of high- and intermediate-risk HPV-16 variants are activated by the cellular transcription factor Brn-3a, whereas the URR of a low-risk HPV-16 variant is not. In this study, we show in transfection assays that Brn-3a and the smoking-related substance nicotine produce stronger responsiveness of the URR of the low- and high-risk variants than with either factor alone, but not the intermediate-risk variant. We determined that this synergistic activity of Brn-3a/nicotine is due to two nucleotide differences in the URR, crucial for oncogenic E6/E7 transactivation. Mutant constructs in which the nucleotide residues were substituted alter Brn-3a/nicotine responsiveness. Importantly, women smokers with high levels of Brn-3a infected with low- or high-risk HPV-16 variants have augmented E6 levels, and were more frequently diagnosed with higher grades of cervical intraepithelial neoplasia (CIN) and cancer, as compared with non-smokers who were infected with similar variants and expressed similar levels of Brn-3a. Therefore, this study defines the specific interplay between the cellular transactivator Brn-3a, the environmental smoking-related substance nicotine and specific HPV variants in cervical carcinogenesis, and thus helps to explain why some women are susceptible to rapid CIN progression and cancer and others are not.

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Abbreviations

URR:

upstream regulatory region

CIN:

cervical intraepithelial neoplasia

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Acknowledgements

This study was funded by the Association for International Cancer Research (AICR).

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Authors and Affiliations

  1. Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK

    D Ndisang, A Khan, M Sindos & D S Latchman

  2. Instituto Materno Infantil de Pernambuco (IMIP), Rua dos Coelhos, Pernambuco, Brazil

    A Khan & A Singer

  3. Department of Women's and Children's Health, The Whittington Hospital, Highgate Hill, London, UK

    F Lorenzato

  4. Birkbeck, University of London, London, UK

    D S Latchman

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  1. D Ndisang
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  2. A Khan
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  3. F Lorenzato
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  4. M Sindos
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  5. A Singer
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  6. D S Latchman
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Correspondence to D Ndisang.

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Ndisang, D., Khan, A., Lorenzato, F. et al. The cellular transcription factor Brn-3a and the smoking-related substance nicotine interact to regulate the activity of the HPV URR in the cervix. Oncogene 29, 2701–2711 (2010). https://doi.org/10.1038/onc.2010.33

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