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TNF-α regulates epithelial expression of MMP-9 and integrin αvβ6 during tumour promotion. A role for TNF-α in keratinocyte migration?

Oncogene volume 23, pages 6954–6966 (2004)Cite this article

Abstract

Mice deficient in TNF-α (TNF-α−/− mice) are resistant to skin carcinogenesis and expression of MMP-9 is inhibited in TNF-α−/− mice during skin tumour development. In the early stages of tumour promotion, MMP-9 protein initially localized to the follicular epidermis but subsequently began to accumulate in the interfollicular epidermis of wild-type but not TNF-α−/− mice. Inhibition of TNF-α or MMP-9 function reduced keratinocyte migration in vitro. In addition, a deficiency of TNF-α delayed re-epithelialization in vivo and this correlated with reduced MMP-9 expression. Collectively, these data suggest that MMP-9 regulates keratinocyte migration in a TNF-α-dependent manner. Expression profiling of genes that control cell adhesion and migration revealed markedly lower levels of the integrin subunits αv and β6 in TNF-α−/− compared with wild-type keratinocytes in vitro. αvβ6 expression was upregulated by keratinocytes in vitro and during tumour promotion in vivo in a TNF-α-dependent manner. Furthermore, αvβ6 blockade significantly inhibited keratinocyte migration and TNF-α-stimulated MMP-9 expression in vitro. These data illustrate a novel TNF-α-dependent mechanism for the control of αvβ6 expression and suggest one pathway for TNF-α regulation of MMP-9. Increased MMP-9 and αvβ6 expression may stimulate epithelial cell migration during tumour formation and may be one mechanism whereby TNF-α acts as an endogenous tumour promoter.

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Acknowledgements

We are grateful to George Elia for histological processing of the skin samples; Nick East for technical assistance; David Owens for several helpful discussions; Caroline Barton, Frances Burke, Lisa Coussens, Kairbaan Hodivala-Dilke and Marian Nakada for critically reviewing this manuscript; Centocor and Cancer Research UK for funding this research.

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Author notes

  1. Kate A Scott

    Present address: Department of Tumour Biology, Cancer Research UK Cancer Centre, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK

Authors and Affiliations

  1. Translational Oncology Laboratory, Cancer Research UK Cancer Centre, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK

    Kate A Scott, Caroline H Arnott, Stephen C Robinson, Robert J Moore, Richard G Thompson & Frances R Balkwill

  2. Department of Tumour Biology, Cancer Research UK Cancer Centre, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK

    John F Marshall

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  1. Kate A Scott
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  2. Caroline H Arnott
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Correspondence to Kate A Scott.

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Scott, K., Arnott, C., Robinson, S. et al. TNF-α regulates epithelial expression of MMP-9 and integrin αvβ6 during tumour promotion. A role for TNF-α in keratinocyte migration?. Oncogene 23, 6954–6966 (2004). https://doi.org/10.1038/sj.onc.1207915

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