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Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo

J R Grandis1, S D Drenning, Q Zeng

  • 1Department of Otolaryngology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. jgrandis+@pitt.edu

Proceedings of the National Academy of Sciences of the United States of America
|April 13, 2000
PubMed

Insights

Constitutively activated STAT3 (Signal Transducer and Activator of Transcription 3) is an early event in head and neck cancer development. Inhibiting STAT3 activation can reduce tumor growth and increase cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Field cancerization increases the risk of multiple primary tumors in the upper aerodigestive tract due to carcinogen exposure.
  • Epidermal growth factor receptor (EGFR) up-regulation is an early event in squamous cell carcinogenesis, crucial for growth control loss in head and neck cancers.
  • EGFR stimulation activates STAT proteins (Signal Transducer and Activator of Transcription) in head and neck squamous cell carcinoma cells.

Purpose of the Study:

  • To investigate the temporal role of STAT3 activation in head and neck carcinogenesis.
  • To compare STAT3 expression and activation in tumors and normal mucosa of head and neck cancer patients versus controls.

Main Methods:

  • Studied STAT3 expression and constitutive activation in head and neck tumors and adjacent normal mucosa from cancer patients and control subjects.
  • Utilized in vivo liposome-mediated gene therapy with a STAT3 antisense plasmid in a head and neck xenograft model.

Main Results:

  • STAT3 was up-regulated and constitutively activated in both head and neck tumors and the adjacent normal mucosa of cancer patients, compared to controls.
  • STAT3 antisense gene therapy inhibited STAT3 activation, increased tumor cell apoptosis, and decreased Bcl-x(L) expression in a xenograft model.

Conclusions:

  • Constitutively activated STAT3 is an early event in head and neck carcinogenesis.
  • Activated STAT3 contributes to the loss of growth control through an anti-apoptotic mechanism.
  • Targeting STAT3 activation holds therapeutic potential for head and neck cancers.

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