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Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis

Keith Syson Chan1, Steve Carbajal, Kaoru Kiguchi

  • 1Department of Carcinogenesis, The University of Texas, M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.

Cancer Research
|April 3, 2004
PubMed

Insights

Signal transducers and activators of transcription (STATs), particularly Stat3, are activated during mouse skin tumor promotion. Stat3 activation, potentially mediated by epidermal growth factor receptor (EGFR), is crucial for keratinocyte proliferation and tumor development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Signal transducers and activators of transcription (STATs) are crucial signaling molecules.
  • STAT3 is implicated in cell proliferation and survival, key processes in cancer development.
  • The role of STAT3 in skin carcinogenesis, particularly its interaction with epidermal growth factor receptor (EGFR), requires further elucidation.

Purpose of the Study:

  • To investigate the role of STATs, especially STAT3, in mouse skin tumor promotion and multistage carcinogenesis.
  • To explore the involvement of epidermal growth factor receptor (EGFR) in modulating STAT3 activity during skin tumor promotion.
  • To determine the functional significance of STAT3 activation in keratinocyte proliferation and skin tumor development.

Main Methods:

  • Activation of Stat1, Stat3, and Stat5 in mouse epidermis following treatment with various tumor promoters (TPA, okadaic acid, chrysarobin).
  • Analysis of STAT activation in skin tumors induced by a two-stage carcinogenesis regimen.
  • Investigating EGFR-STAT3 interactions using primary keratinocyte cultures, transgenic mice, EGFR kinase inhibitors, dominant-negative EGFR expression, immunoprecipitation, and STAT3-deficient mice.

Main Results:

  • Stat1, Stat3, and Stat5 were activated in mouse epidermis by tumor promoters and constitutively activated in skin tumors.
  • EGFR activation in keratinocytes led to STAT3 activation; EGFR inhibition reduced STAT3 activation.
  • Enhanced interaction between EGFR and STAT3 was observed in TPA-treated epidermis and skin papillomas.
  • STAT3 deficiency in mouse epidermis significantly reduced the proliferative response to TPA treatment.

Conclusions:

  • STAT3 activation is a critical event in mouse skin tumor promotion, likely regulating keratinocyte proliferation.
  • EGFR plays a role in STAT3 activation during tumor promotion, potentially through direct interaction and phosphorylation.
  • Constitutive STAT3 activation in papillomas and squamous cell carcinomas suggests its involvement in both tumor development and progression.

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