title: Overexpression of matrix metalloproteinase 1 in dermal fibroblasts from DNA repair-deficient/cancer-prone xeroderma pigmentosum group C patients.
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.
authors.affiliation: Genomes and Cancers, CNRS FRE 2939, Institut Gustave Roussy, Villejuif, France.
authors.forename: M
authors.initials: M
authors.lastname: Fréchet
authors.forename: E
authors.initials: E
authors.lastname: Warrick
authors.forename: C
authors.initials: C
authors.lastname: Vioux
authors.forename: O
authors.initials: O
authors.lastname: Chevallier
authors.forename: A
authors.initials: A
authors.lastname: Spatz
authors.forename: S
authors.initials: S
authors.lastname: Benhamou
authors.forename: A
authors.initials: A
authors.lastname: Sarasin
authors.forename: F
authors.initials: F
authors.lastname: Bernerd
authors.forename: T
authors.initials: T
authors.lastname: Magnaldo
mesh_terms: D004260:DNA Repair; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000201:enzymology* / Q000473:pathology; D014158:Transcription, Genetic; D014983:Xeroderma Pigmentosum / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
chemical_list: D017382:Reactive Oxygen Species; D020781:Matrix Metalloproteinase 1