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.
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.
Kato
Yasumasa
Y
Department of Biochemistry and Molecular Biology, Kanagawa Dental College, Yokosuka 238-8580, Japan. yasumasa@kdcnet.ac.jp
Tsukuda
Mamoru
M
Nagashima
Yoji
Y
Koshika
Shinri
S
Sakai
Naoki
N
Yao
Masahiro
M
Kubota
Yoshinobu
Y
Aoki
Ichiro
I
Colledge
William H
WH
Foidart
Jean-Michel
JM
Hata
Ryu-Ichiro
R
Thompson
Erik W
EW
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
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