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A role for transcription factor STAT3 signaling in oncogene smoothened-driven carcinogenesis

Dongsheng Gu1, Qipeng Fan, Xiaoli Zhang

  • 1Wells Center for Pediatric Research, Departments of Pediatrics, Biochemistry/Molecular Biology and Pharmacology/ Toxicology, The Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46074, USA.

The Journal of Biological Chemistry
|September 21, 2012
PubMed

Insights

The Hedgehog (Hh) pathway activates STAT3 signaling via IL-11/IL-11Rα, driving skin cancer development. Blocking this axis reduces tumor growth, offering potential therapeutic targets for basal cell carcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • The Hedgehog (Hh) pathway is crucial for development and implicated in various cancers, including basal cell carcinoma (BCC).
  • Molecular mechanisms linking Hh pathway activation to carcinogenesis are not fully understood.
  • STAT3 phosphorylation is observed in human BCCs.

Purpose of the Study:

  • To elucidate the molecular mechanisms of Hh pathway-mediated skin carcinogenesis.
  • To investigate the role of IL-11, IL-11Rα, and STAT3 in Hh-driven skin tumors.
  • To assess the therapeutic potential of targeting the IL-11Rα/STAT3 axis.

Main Methods:

  • Generated transgenic mice with oncogenic Smo (SmoM2) expression in the epidermis.
  • Utilized epidermis-specific STAT3 knockout mice.
  • Employed IL-11Rα null mice and neutralizing antibodies for IL-11.
  • Analyzed STAT3 phosphorylation, cell proliferation, stem/progenitor populations, and cyclin D1 expression.
  • Used Hh-responsive cell lines (ES14, C3H10T1/2) treated with Smo agonist purmorphamine and IL-11Rα knockdown.

Main Results:

  • Epidermal SmoM2 expression elevated IL-11, IL-11Rα, and STAT3 phosphorylation (Tyr705).
  • STAT3 phosphorylation was detected in human BCCs, primarily in keratinocytes.
  • Epidermal-specific STAT3 knockout significantly reduced SmoM2-induced proliferation, epidermal thickness, and tumor development.
  • STAT3 knockout also decreased epidermal stem/progenitor cells and cyclin D1 expression.
  • Tumor development was reduced in IL-11Rα null mice and with IL-11 neutralization.
  • Smo agonist induced STAT3 phosphorylation, abolished by IL-11Rα knockdown.

Conclusions:

  • The IL-11Rα/STAT3 signaling axis is critical for Hh pathway-mediated skin carcinogenesis.
  • STAT3 activation, potentially downstream of IL-11/IL-11Rα, drives proliferation and tumor development.
  • Targeting the IL-11Rα/STAT3 axis represents a promising therapeutic strategy for Hh-driven skin cancers.

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