Decreased Smad4 expression in the transforming growth factor-beta signaling pathway during progression of esophageal squamous cell carcinoma

Cancer. 2002 Aug 15;95(4):737-43. doi: 10.1002/cncr.10727.


Background: Transforming growth factor-beta (TGF-beta) has antiproliferative effects in various cells, and inactivation of the TGF-beta signaling pathway contributes to tumor progression or development. Smad4, a tumor suppressor gene, is a central mediator in the signaling pathways of the TGF-beta superfamily. This study was undertaken to clarify the correlation between Smad4 expression and the clinicopathologic characteristics of patients with esophageal squamous cell carcinoma (SCC). The authors also investigated the expression of components of the TGF-beta signaling pathway in seven established cell lines derived from esophageal SCC.

Methods: Immunohistochemistry for Smad4 using monoclonal anti-Smad4 antibody was performed on surgical specimens obtained from 80 patients with esophageal SCC. In seven cell lines, the authors examined the expression of components of the TGF-beta signaling pathway using Western and Northern blot analyses.

Results: There was a significant inverse correlation between Smad4 expression and both depth of invasion (P = 0.0008) and pathologic stage (P = 0.0079). The expression of Smad4 proteins could be detected in five of seven cell lines. The expression of TGF-beta type II receptor protein was decreased in two of seven cell lines, and the expression of both Smad2 and Smad3 proteins was decreased in only one cell line. The level of expression of Smad4 mRNA did not differ dramatically between cell lines and was not correlated with the quantity of Smad4 protein.

Conclusions: In this study, the expression of Smad4 protein appeared to be correlated with the depth of invasion of esophageal SCC. The loss of Smad4 expression was not regulated at the level of transcription.

MeSH terms

  • DNA-Binding Proteins / metabolism*
  • Esophageal Neoplasms / metabolism*
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Neoplasm Invasiveness
  • Neoplasms, Squamous Cell / metabolism*
  • Smad4 Protein
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Tumor Cells, Cultured


  • DNA-Binding Proteins
  • SMAD4 protein, human
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta