Differential function of STAT5 isoforms in head and neck cancer growth control.
Up-regulation of the epidermal growth factor receptor (EGFR) is critical for the loss of growth control in a variety of human cancers, including squamous cell carcinoma of the head and neck (SCCHN). Stimulation of EGFR results in activation of mitogenic signaling pathways including Signal Transducers and Activators of Transcription (STATs). Stat5 activation has been primarily demonstrated in hematopoietic malignancies. Gene disruption studies suggest potentially distinct functions of the Stat5 isoforms, Stat5a and Stat5b, which are encoded by two genes closely linked on human chromosome 17. To determine the function of Stat5 in SCCHN growth control, we studied the expression and constitutive activation of Stat5a and Stat5b in normal and transformed human squamous epithelial cells. Increased constitutive activation of Stat5 was detected in transformed compared with normal squamous cells. Blockade of TGF-alpha or EGFR, abrogated Stat5 activation. Targeting of Stat5b using antisense oligonucleotides inhibited SCCHN growth. In addition, SCCHN cells stably transfected with dominant negative mutant Stat5b failed to proliferate in vitro. In contrast, targeting of Stat5a using either antisense or dominant negative strategies had no effect on cell growth. These results suggest that TGF-alpha/EGFR-mediated autocrine growth of transformed epithelial cells is dependent on activation of Stat5b but not Stat5a.
Leong
Paul L
PL
Department of Otolaryngology, The University of Pittsburgh School of Medicine and The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Xi
Sichuan
S
Drenning
Stephanie D
SD
Dyer
Kevin F
KF
Wentzel
Abbey L
AL
Lerner
Edwina C
EC
Smithgall
Thomas E
TE
Grandis
Jennifer Rubin
JR
D002294:Carcinoma, Squamous Cell; D002455:Cell Division; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D006258:Head and Neck Neoplasms; D006801:Humans; D008894:Milk Proteins; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D020033:Protein Isoforms; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors