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[Cancer Research 63, 5629-5635, September 1, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Epidermal Growth Factor Receptor-stimulated Activation of Phospholipase C{gamma}-1 Promotes Invasion of Head and Neck Squamous Cell Carcinoma1

Sufi Mary Thomas, Francesca M. Coppelli, Alan Wells, William E. Gooding, John Song, Jareer Kassis, Stephanie D. Drenning and Jennifer Rubin Grandis2

Departments of Otolaryngology [S. M. T., F. M. C., J. S., S. D. D., J. R. G.], Pharmacology [J. R. G.], Pathology [A. W., J. K.], and Biostatistics [W. E. G.], University of Pittsburgh, University of Pittsburgh Cancer Institute, and Pittsburgh Veterans’ Administration Medical Center [A. W., J. K.], Pittsburgh, Pennsylvania 15213

Lymph node metastasis and local invasion of head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis. However, little is known about the factors governing tumor cell invasion in HNSCC. Phospholipase C{gamma}-1 (PLC{gamma}-1) contributes to tumor cell invasion in experimental systems when activated by the epidermal growth factor receptor (EGFR). We hypothesized that EGFR overexpression in HNSCC mediates invasion via PLC{gamma}-1. On EGFR ligand stimulation, phosphorylation of PLC{gamma}-1 increased in all of the HNSCC cell lines tested (4 of 4). In the presence of EGFR-specific tyrosine kinase inhibitor (PD153035) or an anti-EGFR antibody (C225), PLC{gamma}-1 activation was abrogated indicating that PLC{gamma}-1 was downstream of EGFR. Blocking cellular PLC with an inhibitor (U73122) reduced inositol phosphate turnover in all of the HNSCC cell lines examined, and treatment with the PLC inhibitor or antisense oligonucleotides targeting PLC{gamma}-1 significantly reduced in vitro invasiveness of HNSCC cell lines through Matrigel. To determine the clinical relevance of these findings, we compared levels of PLC{gamma}-1 in tumor and paired normal tissue from 33 patients with HNSCC. PLC{gamma}-1 levels were significantly higher (P < 0.0001) in the tumors compared with the normal mucosa of HNSCC patients. Levels of activated PLC{gamma}-1 were analyzed in 20 patients. Tumors expressed higher levels of phosphorylated PLC{gamma}-1 compared with normal adjacent mucosa (P = 0.05). Thus, PLC{gamma}-1 may mediate invasion and metastasis downstream of EGFR in HNSCC.




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