Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis
Keith Syson Chan, … , Junji Takeda, John DiGiovanni
Keith Syson Chan, … , Junji Takeda, John DiGiovanni
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):720-728. https://doi.org/10.1172/JCI21032.
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Article Oncology

Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis

Abstract

Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been found in a wide spectrum of human malignancies. Here, we have assessed the effect of Stat3 deficiency on skin tumor development using the 2-stage chemical carcinogenesis model. The epidermis of Stat3-deficient mice showed a significantly reduced proliferative response following treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) because of a defect in G1-to-S-phase cell cycle progression. Treatment with the tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) resulted in a significant increase in the number of keratinocyte stem cells undergoing apoptosis in the bulge region of hair follicles of Stat3-deficient mice compared with nontransgenic littermates. Notably, Stat3-deficient mice were completely resistant to skin tumor development when DMBA was used as the initiator and TPA as the promoter. Abrogation of Stat3 function using a decoy oligonucleotide inhibited the growth of initiated keratinocytes possessing an activated Ha-ras gene, both in vitro and in vivo. In addition, injection of Stat3 decoy into skin tumors inhibited their growth. To our knowledge, these data provide the first evidence that Stat3 is required for de novo epithelial carcinogenesis, through maintaining the survival of DNA-damaged stem cells and through mediating and maintaining the proliferation necessary for clonal expansion of initiated cells during tumor promotion. Collectively, these data suggest that, in addition to its emerging role as a target for cancer therapy, Stat3 may also be a target for cancer prevention strategies.

Authors

Keith Syson Chan, Shigetoshi Sano, Kaoru Kiguchi, Joanne Anders, Nobuyasu Komazawa, Junji Takeda, John DiGiovanni

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Analysis of cell cycle regulatory proteins in Stat3-deficient mice follo...
Analysis of cell cycle regulatory proteins in Stat3-deficient mice following treatment with TPA. (A–D) Groups of mice (n = 3) were treated with a single application of 6.8 nmol TPA and sacrificed at various times thereafter, as indicated. BrdU was injected 30 minutes prior to sacrifice. (A) Percentage of BrdU-positive epidermal basal cells in control (solid line) and Stat3-deficient (broken line) mice. (B) Immunohistochemical analysis of p-Stat3 localization in skin sections from Stat3-deficient mice (–/–) and control littermates (+/+) with (lower panels) or without (upper panels) TPA treatment. Positive staining for tyrosine-phosphorylated Stat3 in the nuclei of epidermal keratinocytes is shown by brown staining. Arrows, positive signals found in dermal cells such as fibroblasts and macrophages. Scale bar: 50 μm. (C) Western blot analyses of Stat3 and tyrosine-phosphorylated Stat3 protein levels in relation to levels of cyclin D1, cyclin E, and c-Myc at different time points in control and Stat3-deficient mouse epidermis following TPA treatment. (D) Semiquantitative analysis of the mRNA levels of cyclin D1 and c-Myc without treatment and 4 hours after TPA treatment. (E) Western blot analysis of Erk1/2 and phosphorylated Erk1/2 levels at different time points following TPA treatment in epidermis of control and Stat3-deficient mice.