Abstract
The role of the TGF-beta-Smad signaling pathway in the carcinogenesis of head and neck cancer has not been fully evaluated genetically. In this study, we screened for mutation in the five main members of the TGF-beta -Smad signaling pathway, TGF-beta type I receptor (TGFBRI), TGF-beta type II receptor (TGFBRII), SMAD2, SMAD3 and SMAD4, in eight human head and neck squamous cell carcinoma (HNSCC) cell lines. Two mutations with presumed loss of heterozygosity (LOH) were identified. A novel missense mutation of SMAD2, located in exon 8 at codon 276 TCG (ser) -->TTG (leu), was identified in cell line SCC-15. This is the first report of a biallelic mutation of the SMAD2 gene in HNSCC. A nonsense mutation of the SMAD4 gene in exon 5 codon 245 CAG (glut) -->TAG (stop) was found in cell line CAL27. Western blotting verified that this nonsense mutation gives rise to the complete loss of the Smad4 protein in the cells. While the down-regulation and loss of expressions of the TGF-beta-Smad signaling pathway have been described frequently in HNSCC, here we offer further genetic evidence that the pathway is directly targeted for mutation during the HNSCC tumorigenesis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Activin Receptors, Type I / genetics
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Base Sequence
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Blotting, Western
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / pathology
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Carcinoma, Squamous Cell / physiopathology
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Cell Line, Tumor
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Codon, Nonsense
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DNA Mutational Analysis
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Gene Expression Regulation, Neoplastic
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Head and Neck Neoplasms / genetics
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Head and Neck Neoplasms / pathology
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Head and Neck Neoplasms / physiopathology
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Humans
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Loss of Heterozygosity
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Mutation*
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Mutation, Missense
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Polymorphism, Genetic
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Smad Proteins / genetics*
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Smad Proteins / metabolism
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Smad4 Protein / genetics
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Smad4 Protein / metabolism
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Transforming Growth Factor beta / physiology*
Substances
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Codon, Nonsense
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Smad2 Protein
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Smad3 Protein
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Smad4 Protein
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II