title: Reduced excision repair cross-complementing 1 expression associates with enhanced papilloma formation and fibroblast transformation after genetic disruption of secreted protein acidic and rich in cysteine.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Kanagawa Dental College, Yokosuka 238-8580, Japan. yasumasa@kdcnet.ac.jp
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kato
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tsukuda
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Shinri
authors.initials: S
authors.lastname: Koshika
authors.forename: Naoki
authors.initials: N
authors.lastname: Sakai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kubota
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aoki
authors.forename: William H
authors.initials: WH
authors.lastname: Colledge
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Ryu-Ichiro
authors.initials: R
authors.lastname: Hata
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005838:Genotype; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D015676:Osteonectin / Q000235:genetics* / Q000378:metabolism; D010212:Papilloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D013997:Time Factors
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D015676:Osteonectin; D012333:RNA, Messenger; D015127:9,10-Dimethyl-1,2-benzanthracene; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D013755:Tetradecanoylphorbol Acetate