Document Detail

Direct evidence for the critical role of NFAT3 in benzo[a]pyrene diol-epoxide-induced cell transformation through mediation of inflammatory cytokine TNF induction in mouse epidermal Cl41 cells.
MedLine Citation:
PMID:  17522069     Owner:  NLM     Status:  MEDLINE    
Nuclear factor of activated T cell (NFAT)-3 is a member of the transcription factor NFAT family, which has been demonstrated to be responsible for the up-regulation of the pro-inflammatory cytokine tumor necrosis factor (TNF) in the immune system. Our most recent studies have also shown that TNF is able to induce cell transformation in mouse epidermal Cl41 cells by induction of cyclooxygenase-2 (COX-2) expression. To provide direct evidence for NFAT3 in the environmental carcinogen-caused carcinogenic effect, (+/-)-benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), an ultimate environmental carcinogen metabolized from benzo[a]pyrene, was utilized. We found that exposure of Cl41 cells to B[a]PDE was able to induce cell transformation in Cl41 cells, while specific knock-down of NFAT3 resulted in the dramatic inhibition of this cell transformation. The tumorigenicity of B[a]PDE-caused transformed cells was confirmed in nude mice, whereas the tumor formation of B[a]PDE-treated NFAT3 small interference RNA (siRNA) knock-down cells was significantly reduced. Further studies showed that the role of NFAT3 in B[a]PDE-caused cell transformation was mediated by up-regulation of its downstream targeted gene TNF. This conclusion was based on the findings that inhibition of NFAT3 activation by either FK506 or NFAT3 siRNA dramatically down-regulated the TNF induction upon B[a]PDE exposure, and that knock-down of TNF by its specific siRNA also led to abrogation of B[a]PDE-induced cell transformation in Cl41 cells and their tumorigenicity in nude mice. Collectively, these results provide direct evidence for the important role of NFAT3 activation in B[a]PDE-induced cell transformation by up-regulation of TNF expression in mouse epidermal Cl41 cells, further suggesting that B[a]PDE may exert its tumor promotion effect on skin carcinogenesis, at least partially, by inducing TNF expression.
Weiming Ouyang; Yu Hu; Jingxia Li; Min Ding; Yongju Lu; Dongyun Zhang; Yan Yan; Lun Song; Qingshan Qu; Dhimant Desai; Shantu Amin; Chuanshu Huang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-05-23
Journal Detail:
Title:  Carcinogenesis     Volume:  28     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-10-08     Completed Date:  2007-12-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  2218-26     Citation Subset:  IM    
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
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MeSH Terms
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / toxicity*
Cell Division
Cell Line
Cell Transformation, Neoplastic*
Epidermis / drug effects,  physiology*
Genes, Reporter
Genetic Vectors
Mice, Nude
NFATC Transcription Factors / genetics,  physiology*
RNA, Small Interfering / genetics
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha / genetics*
Grant Support
Reg. No./Substance:
0/NFATC Transcription Factors; 0/RNA, Small Interfering; 0/Tumor Necrosis Factor-alpha; 55097-80-8/7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide

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