Loss of p12CDK2-AP1 expression in human oral squamous cell carcinoma with disrupted transforming growth factor-beta-Smad signaling pathway.
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.
Peng
Hui
H
Dental Research Institute, School of Dentistry, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Shintani
Satoru
S
Kim
Yong
Y
Wong
David T
DT
D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D051899:Smad2 Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
C096151:CDK2AP1 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2