Epidermal growth factor receptor-mediated Stat3 signaling blocks apoptosisin head and neck cancer

Objectives: Upregulation of epidermal growth factor receptor (EGFR) is crit ical 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 i n culture, EGFR stimulation initiates signaling via persistent activation o f STAT proteins, particularly Stat3, The present study was conducted to stu dy the association between EGFR stimulation and constitutive activation of Stat3 in SCCHN in vivo and to investigate the proliferative and apoptotic c onsequences 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, re spectively. Results: In vivo liposome mediated gene therapy with an EGFR an tisense plasmid efficiently inhibited Stat3 activation in a head and neck x enograft model. Downmodulation of Stat3 using a dominant-negative or antise nse approach inhibited tumor cell growth and stimulated apoptosis, Conclusi ons: These findings provide evidence that constitutively activated Stat3 is Linked to EGFR signaling in SCCHN in vivo, which contributes to the loss o f growth control by an anti-apoptotic mechanism.