Loss of p12CDK2-AP1 expression in human oral squamous cell carcinoma with disrupted transforming growth factor-beta-Smad signaling pathway

Neoplasia. 2006 Dec;8(12):1028-36. doi: 10.1593/neo.06580.


We examined correlations between TGF-beta1, TbetaR-I and TbetaR-II, p12(CDK2-AP1), p21(WAF1), p27(KIP1), Smad2, and p-Smad2 in 125 cases of human oral squamous cell carcinoma (OSCC) to test the hypothesis that resistance to TGF-beta1-induced growth suppression is due to the disruption of its signaling pathway as a consequence of reduced or lost p12(CDK2-AP1). Immunoreactivity for TbetaR-II decreased in OSCC with increasing disease aggressiveness; however, no differences were observed for TbetaR-I and TGF-beta1. The expression of TbetaR-II significantly correlated with p12(CDK2-AP1) and p27(KIP1) (P < .001 and P < .01, respectively). Furthermore, there was a significant relationship between TbetaR-II expression and p-Smad2 (P < .001). The in vivo correlation of the levels of TbetaR-II, p12(CDK2-AP1), and p27(KIP1) was confirmed in normal and OSCC cell lines. Additionally, in vitro analysis of TGF-beta1-treated cells showed that TGF-beta1 treatment of normal keratinocytes suppressed cell growth with upregulation of p-Smad2, p12(CDK2-AP1), and p21(WAF1) expression, whereas there was no effect on OSCC cell lines. These results provide evidence of a link between a disrupted TGF-beta-Smad signaling pathway and loss of induction of cell cycle-inhibitory proteins, especially p12(CDK2-AP1) in OSCC, which may lead to the resistance of TGF-beta1 growth-inhibitory effect on OSCC.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 2 / biosynthesis
  • Cyclin-Dependent Kinase 2 / deficiency*
  • Cyclin-Dependent Kinase 2 / genetics
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Middle Aged
  • Mouth Neoplasms / genetics
  • Mouth Neoplasms / metabolism*
  • Signal Transduction / genetics*
  • Smad2 Protein / biosynthesis
  • Smad2 Protein / genetics
  • Smad2 Protein / physiology*
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / physiology
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics


  • CDK2AP1 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2