Abstract
SPARC (secreted protein acidic and rich in cysteine)/ osteonectin/BM-40 is a matricellular protein implicated in development, cell transformation and tumorigenesis. We have examined the role of SPARC in cell transformation induced chemically with 7,12-dimethylbenz[a]anthracene (DMBA) and 12-tetradecanoylphorbol-13-acetate (TPA) in embryonic fibroblasts and in the skin of mice. Embryonic fibroblasts from SPARCnull mice showed increases in cell proliferation, enhanced sensitivity to DMBA and a higher number of DMBA/TPA-induced transformation foci. The number of DMBA-DNA adducts was 9 times higher in SPARCnull fibroblasts and their stability was lower than wild-type fibroblasts, consistent with a reduction in excision repair cross-complementing 1 the nucleotide excision repair enzyme in these cells. The SPARCnull mice showed an increase in both the speed and number of papillomas forming after topical administration of DMBA/TPA to the skin. These papillomas showed reduced growth and reduced progression to a more malignant phenotype, indicating that the effect of SPARC on tumorigenesis depends upon the transformation stage and/or tissue context. These data reinforce a growing number of observations in which SPARC has shown opposite effects on different tumor types/stages.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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9,10-Dimethyl-1,2-benzanthracene / chemistry
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9,10-Dimethyl-1,2-benzanthracene / toxicity
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Animals
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Carcinogens / toxicity
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / pathology
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Cells, Cultured
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DNA Adducts / chemistry
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DNA Adducts / metabolism
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian / cytology
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Endonucleases / genetics*
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Endonucleases / metabolism
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Female
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Gene Expression / drug effects
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Genotype
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Male
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Osteonectin / genetics*
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Osteonectin / metabolism
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Papilloma / genetics
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Papilloma / metabolism
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Papilloma / pathology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Skin / drug effects
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Skin / metabolism
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Skin / pathology
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Tetradecanoylphorbol Acetate / toxicity
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Time Factors
Substances
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Carcinogens
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DNA Adducts
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DNA-Binding Proteins
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Osteonectin
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RNA, Messenger
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9,10-Dimethyl-1,2-benzanthracene
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Endonucleases
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Ercc1 protein, mouse
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Tetradecanoylphorbol Acetate