Carcinogenesis Advance Access published online on May 2, 2008
Carcinogenesis, doi:10.1093/carcin/bgn061
Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis
1 Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
2 Department of Biochemistry, Louisiana State University–Health Science Center, Shreveport, Louisiana, USA
3 These authors contributed equally to this work
* To whom correspondence should be addressed: John DiGiovanni, 1808 Park Road 1C, PO Box 389, Smithville, TX 78957, E-mail: jdigiovanni{at}sprd1.mdacc.tmc.edu, Tel: 512-237-9414, Fax: 512-237-2522
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 (TPA). 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 i.p. injection) led to inhibition of tumor growth compared to 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.
Key Words: Stat3 • skin carcinogenesis • tumor initiation • tumor promotion
Received November 26, 2007; revised February 20, 2008; accepted February 24, 2008.