Alterations of Smad Expression and Activation in Defining 2 Subtypes of Human Head and Neck Squamous Cell Carcinoma

Head Neck. 2013 Jan;35(1):76-85. doi: 10.1002/hed.22924. Epub 2012 Jan 24.


Background: We postulated that disruptions of the canonical transforming growth factor-beta (TGF-β)/Smad signaling pathway might contribute to the development of head and neck squamous cell carcinoma (HNSCC).

Methods: A cohort of 798 HNSCC tumor samples from 346 patients were analyzed by immunohistochemistry (IHC) to define the pattern of expression of (phospho)Smad2, (phospho)Smad3, and Smad4.

Results: We found that 19%, 40%, and 12% of HNSCC specimens failed to express pSmad2, pSmad3, or Smad4, respectively. Loss of Smad2/3 activation was observed in 8.5% of specimens. In addition, 4% of specimens failed to express only Smad4. Moreover, patients with pSmad2/3-negative tumors had a significantly better overall survival than that of those whose tumors expressed activated Smad2/3. In contrast, loss of Smad4 expression did not have prognostic significance.

Conclusion: Our results indicate that HNSCC in which Smad2/3 are inactivated or in which Smad4 expression is lost represent 2 distinct tumor subtypes with different clinical outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Squamous Cell / metabolism*
  • Female
  • Head and Neck Neoplasms / metabolism*
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Prognosis
  • Signal Transduction
  • Smad Proteins / biosynthesis*
  • Squamous Cell Carcinoma of Head and Neck
  • Survival Analysis
  • Tissue Array Analysis
  • Transforming Growth Factor beta / metabolism*


  • Smad Proteins
  • Transforming Growth Factor beta