Epidermal growth factor receptor--mediated stat3 signaling blocks apoptosis in head and neck cancer.
OBJECTIVE
Upregulation of epidermal growth factor receptor (EGFR) is critical for the loss of growth control in a variety of human cancers including squamous cell cancers of the head and neck (SCCHN). In these tumor cells in culture, EGFR stimulation initiates signaling via persistent activation of STAT proteins, particularly Stat3. The present study was conducted to study the association between EGFR stimulation and constitutive activation of Stat3 in SCCHN in vivo and to investigate the proliferative and apoptotic consequences of Stat3 downmodulation in SCCHN cells in vitro.


METHODS
SCCHN tumor xenografts were analyzed using electrophoretic mobility shift assay. A dominant-negative mutant Stat3 expression construct or a Stat3 antisense plasmid was transfected into SCCHN cells using lipofectamine. Cell growth and apoptosis were determined by vital dye exclusion and flow cytometry, respectively.


RESULTS
In vivo liposome-mediated gene therapy with an EGFR antisense plasmid efficiently inhibited Stat3 activation in a head and neck xenograft model. Downmodulation of Stat3 using a dominant-negative or antisense approach inhibited tumor cell growth and stimulated apoptosis.


CONCLUSIONS
These findings provide evidence that constitutively activated Stat3 is linked to EGFR signaling in SCCHN in vivo, which contributes to the loss of growth control by an anti-apoptotic mechanism.
Rubin Grandis
J
J
University of Pittsburgh School of Medicine, Department of Otolaryngology, Pennsylvania, USA. jgrandis+@pitt.edu
Zeng
Q
Q
Drenning
S D
SD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology*; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010039:Otorhinolaryngologic Neoplasms / Q000473:pathology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000473:pathology*
D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D066246:ErbB Receptors