A novel mechanism of skin tumor promotion involving interferon-gamma (IFNγ)/signal transducer and activator of transcription-1 (Stat1) signaling.
The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during tumor promotion using the mouse skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNγ) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNγ signaling. Stat1 deficient (Stat1(-/-) ) mice were highly resistant to skin tumor promotion by CHRY. In contrast, the tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1(-/-) mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with skin tumor promotion by the anthrone class of tumor promoters involving upregulation of IFNγ signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1.
Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas.|Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
Ronald
R
Bozeman
Department of Carcinogenesis, Science Park-Research Division, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
Erika L
EL
Abel
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
Everardo
E
Macias
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
Tianyi
T
Cheng
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
Linda
L
Beltran
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas.|Department of Nutritional Sciences, College of Natural Sciences, The University of Texas at Austin, Austin, Texas.
John
J
DiGiovanni
D000818:Animals; D000873:Anthracenes / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D000873:Anthracenes; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C013883:chrysarobin; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate
IFNγ; IRF-1; Stat1; epithelial tumorigenesis; inflammation; tumor promotion