Overexpression of matrix metalloproteinase 1 in dermal fibroblasts from DNA repair-deficient/cancer-prone xeroderma pigmentosum group C patients.
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.
Fréchet
M
M
Genomes and Cancers, CNRS FRE 2939, Institut Gustave Roussy, Villejuif, France.
Warrick
E
E
Vioux
C
C
Chevallier
O
O
Spatz
A
A
Benhamou
S
S
Sarasin
A
A
Bernerd
F
F
Magnaldo
T
T
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
D017382:Reactive Oxygen Species; D020781:Matrix Metalloproteinase 1