Carcinogenesis Advance Access originally published online on May 2, 2008
Carcinogenesis 2008 29(6):1108-1114; doi:10.1093/carcin/bgn061
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Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis
Department of Carcinogenesis, Science Park-Research Division, The University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA
1 Department of Biochemistry and Molecular Biology, Louisiana State University Health Science Center, Shreveport, LA 78098, USA
* To whom correspondence should be addressed. Department of Carcinogenesis, Science Park-Research Division, The University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, PO Box 389, Smithville, TX 78957, USA. Tel: +1 512 237 9414; Fax: +1 512 237 2522; Email: jdigiovanni{at}sprd1.mdacc.tmc.edu
Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been found in a variety of human malignancies and has been suggested to play an important role in carcinogenesis. Recently, our laboratory demonstrated that Stat3 is required for the development of skin tumors via two-stage carcinogenesis using skin-specific loss-of-function transgenic mice. To investigate further the role of Stat3 in each stage of chemical carcinogenesis in mouse skin, i.e. initiation and promotion stages, we generated inducible Stat3-deficient mice (K5.Cre-ERT2 x Stat3fl/fl) that show epidermal-specific disruption of Stat3 following topical treatment with 4-hydroxytamoxifen (TM). The epidermis of inducible Stat3-deficient mice treated with TM showed a significant increase in apoptosis induced by 7,12-dimethylbenz[a]anthracene (DMBA) and reduced proliferation following exposure to 12-O-tetradecanoylphorbol-13-acetate. In two-stage skin carcinogenesis assays, inducible Stat3-deficient mice treated with TM during the promotion stage showed a significant delay of tumor development and a significantly reduced number of tumors compared with control groups. Inducible Stat3-deficient mice treated with TM before initiation with DMBA also showed a significant delay in tumor development and a significantly reduced number of tumors compared with control groups. Finally, treatment of inducible Stat3-deficient mice that had existing skin tumors generated by the two-stage carcinogenesis protocol with TM (by intraperitoneal injection) led to inhibition of tumor growth compared with tumors formed in control groups. Collectively, these results directly demonstrate that Stat3 is required for skin tumor development during both the initiation and promotion stages of skin carcinogenesis in vivo.
Abbreviations: BrdU, 5-bromo-2-deoxyuridine; DMBA, 7,12-dimethylbenz[a]anthracene; i.p., intraperitoneal; PBS, phosphate-buffered saline; PPAR
, peroxisome proliferator-activated receptor ; Stat3, signal transducer and activator of transcription 3; TM, 4-hydroxytamoxifen; TPA, 12-O-tetradecanoylphorbol-13-acetate
These authors contributed equally to this work. Received November 26, 2007; revised February 20, 2008; accepted February 24, 2008.
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