Downmodulation of TGF-alpha protein expression with antisense oligonucleotides inhibits proliferation of head and neck squamous carcinoma but not normal mucosal epithelial cells

J Cell Biochem. 1998 Apr 1;69(1):55-62.


Interruption of an autocrine growth pathway involving TGF-alpha and EGFR may inhibit tumor growth and improve survival in head and neck cancer patients. We previously demonstrated that biopsy specimens and established cell lines from patients with squamous cell carcinoma of the head and neck (SCCHN) overexpress TGF-alpha and its receptor, epidermal growth factor receptor (EGFR) at both the mRNA and protein levels. Protein localization studies showed that TGF-alpha and EGFR are produced by the same epithelial cells in tissues from head and neck cancer patients further supporting a role for this ligand-receptor pair in an autocrine growth pathway. To confirm that TGF-alpha contributes to autocrine growth, we examined the effect of down regulation of TGF-alpha protein on SCCHN cell proliferation. Treatment of 6 SCCHN cell lines with antisense oligodeoxynucleotides targeting the translation start site of human TGF-alpha mRNA decreased TGF-alpha protein production by up to 93% and reduced cell proliferation by a mean of 76.2% compared to a 9.7% reduction with sense oligonucleotide (range P = 0.036-0.0001). TGF-alpha antisense oligonucleotide exposure also decreased TGF-alpha protein levels in normal oropharyngeal mucosal epithelial cells, however their growth rate was not affected. These findings indicate that TGF-alpha is participating in an autocrine signaling pathway in transformed, but not in normal mucosal epithelial cells, that promotes proliferation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / pathology
  • Cell Division / drug effects
  • Cell Transformation, Neoplastic
  • Down-Regulation
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Humans
  • Mucous Membrane / cytology
  • Mucous Membrane / drug effects
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / pharmacology
  • Signal Transduction
  • Transforming Growth Factor alpha / genetics*
  • Transforming Growth Factor alpha / metabolism*
  • Tumor Cells, Cultured


  • Oligonucleotides, Antisense
  • Transforming Growth Factor alpha