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Amplification of Wild-Type K-ras Promotes Growth of Head and Neck Squamous Cell Carcinoma¹

Departments of Otolaryngology—Head and Neck Surgery [M. H., S. L. D., S. J. A., R. A. S.] and Biochemistry [R. A. S.], Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts 02118

In contrast to many other tumors of different lineage, oncogenic ras mutations are rarely found within head and neck squamous cell carcinoma (HNSCC). On the other hand, increased expression of wild-type K-ras in HNSCC tumor material has been noticed, but the potential physiological consequences of this observation have not yet been experimentally assessed. The current study addresses this issue by modulating K-ras expression in HNSCC cell lines and primary keratinocytes and determining its effects on cell growth and survival in vitro. Consistent with earlier reports using patient tumor material, Western blot analysis of four HNSCC lines (SCC-9, SCC-15, SCC-25, and FaDu) revealed varying but universally increased protein expression of K-ras relative to keratinocytes. All HNSCC lines expressed wild-type K-ras mRNA based on a random sequencing of eight K-ras cDNA samples obtained by reverse transcription-PCR from each HNSCC line (P 0.00391). Transfection of keratinocytes with a plasmid expression vector containing wild-type K-ras cDNA resulted in dramatically increased proliferation and survival compared with control-transfected or untransfected keratinocytes. Conversely, transfection of FaDu cells, which express the highest level of endogenous K-ras, with K-ras antisense oligonucleotides but not control oligonucleotides significantly reduced cellular proliferation (P 0.0022). These results show that the level of K-ras protein expression is a major determinant of proliferation of HNSCC cells and keratinocytes and suggest that amplification of nonmutated K-ras in HNSCC contributes to tumor growth. These novel findings may have important ramifications for potential K-ras-targeted interventions in the treatment of HNSCC.

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