Abstract
Xeroderma pigmentosum (XP) is a rare, recessively inherited genetic disease characterized by skin cancer proneness and premature aging in photoexposed area. The disease results from defective nucleotide excision repair of ultraviolet (UV)-induced DNA lesions. Reconstruction of group C (XP-C) skin in vitro previously suggested that patients' dermal fibroblasts might be involved in promoting skin cancer development, as they elicited microinvasions of both control and XP-C keratinocytes within dermal equivalents. Here we show that in the absence of UV exposure XP-C fibroblasts exhibit aged-like features such as an elongated and dendritic shape. We analysed the repertoire of expression of matrix metalloproteinases (MMPs) involved in skin aging and cancer. All XP-C fibroblasts tested in this study overexpressed specifically and significantly MMP1. MMP1 expression was also found increased in the dermis of XP-C skin sections suggesting the active contribution of XP-C mesenchymal cells to skin aging and exacerbated carcinogenesis. Increased MMP1 expression in cultured XP-C fibroblasts resulted from MMP1 mRNA accumulation and enhanced transcriptional activity of the MMP1 gene promoter. Deletion analysis revealed the essential role of AP-1 activation in constitutive MMP1 overexpression in XP-C primary fibroblasts. In parallel, levels of reactive oxygen species and FOSB DNA-binding activity were found increased in XP-C fibroblasts. Altogether, these observations suggest that beyond its role in nucleotide excision repair the XPC protein may be important in cell metabolism and fate in the absence of UV.
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Acknowledgements
Dr Asselineau and Dr J Leclaire are gratefully acknowledged for continuous support and encouragements. We are indebted to V Marty, C Pierrard and Dr C Marionnet for their expert help. We are also grateful to Dr A Jalil for confocal microscopy. We thank Professor P Herrlich and Professor CE Brinckerhoff for DNA reporter constructs. Many thanks to F Duvigneau for editing English usage in the article. TM gratefully acknowledges fundings from the Association pour la Recherche sur le Cancer (no. 3590), the Fondation de l'Avenir, the Société Française de Dermatologie, the Association Française contre les Myopathies. AS thanks the association ‘Les enfants de la Lune’ for its support.
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Fréchet, M., Warrick, E., Vioux, C. et al. Overexpression of matrix metalloproteinase 1 in dermal fibroblasts from DNA repair-deficient/cancer-prone xeroderma pigmentosum group C patients. Oncogene 27, 5223–5232 (2008). https://doi.org/10.1038/onc.2008.153
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DOI: https://doi.org/10.1038/onc.2008.153