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Tumour necrosis factor-α mediates tumour promotion via a PKCα- and AP-1-dependent pathway

Oncogene volume 21, pages 4728–4738 (2002)Cite this article

Abstract

Tumour necrosis factor-α (TNF-α) deficient mice (TNF-α−/− mice) are resistant to skin carcinogenesis. Cellular signalling via the transcription factor complex AP-1 is thought to play a key role in tumour promotion. The induction of a specific subset of AP-1 responsive genes thought to be important for tumour development, namely GM–CSF, MMP-9 and MMP-3, was suppressed in TNF-α−/− compared to wild-type mouse skin in response to the tumour promotor TPA. The differential induction of these genes correlated with a temporal shift in AP-1 activation and c-Jun expression in TNF-α−/− compared to wild-type epidermis. The major receptor for TPA-induced signalling in basal keratinocytes, PKCα, was also differentially regulated in wild-type compared with TNF-α−/− epidermis. A marked delay in TPA-induced intracellular translocation and downregulation of PKCα was observed in TNF-α−/− epidermis, which correlated with the deregulated TPA-induced AP-1 activation and c-Jun expression. The frequency of DNA adduct formation and c-Ha-ras mutations was the same in wild-type and TNF-α−/− epidermis after DMBA treatment, suggesting that TNF-α was not involved in tumour initiation. These data suggest that the pro-inflammatory cytokine TNF-α is a critical mediator of tumour promotion, acting via a PKCα- and AP-1-dependent pathway. This may be one mechanism by which chronic inflammation increases susceptibility to cancer.

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Acknowledgements

The authors would like to thank George Kollias and Manolis Pasparakis for originally supplying us with TNF-α−/− mice; Nick East and Hazel Holdsworth for technical assistance; Stephen Robinson and Lala Khalique for help with Real-time RT–PCR; and Fiona Watt for advice with the manuscript. DM Owens was supported by the National Research Service Award CA75638 from the National Cancer Institute. Alan Hewer and David Phillips were supported by the Cancer Research Campaign.

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Authors and Affiliations

  1. Cancer Research UK Translational Oncology Laboratory, Bart's and The London School of Medicine and Dentistry, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK

    Caroline H Arnott, Kate A Scott, Robert J Moore & Frances R Balkwill

  2. Institute of Cancer Research, Haddow Laboratories, Cotswold Road, Sutton, Surrey, SM2 5NG, UK

    Alan Hewer & David H Phillips

  3. Protein Phosphorylation Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Peter Parker

  4. Keratinocyte Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    David M Owens

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  1. Caroline H Arnott
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Correspondence to Frances R Balkwill.

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Arnott, C., Scott, K., Moore, R. et al. Tumour necrosis factor-α mediates tumour promotion via a PKCα- and AP-1-dependent pathway. Oncogene 21, 4728–4738 (2002). https://doi.org/10.1038/sj.onc.1205588

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