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

Abstract

We examined correlations between TGF-β1, TβR-I and TβR-II, p12CDK2-AP1, p21WAF1, p27KIP1, Smad2, and p-Smad2 in 125 cases of human oral squamous cell carcinoma (OSCC) to test the hypothesis that resistance to TGF-β1-induced growth suppression is due to the disruption of its signaling pathway as a consequence of reduced or lost p12CDK2-AP1. Immunoreactivity for TβR-II decreased in OSCC with increasing disease aggressiveness; however, no differences were observed for TβR-I and TGF-β1. The expression of TβR-II significantly correlated with p12CDK2-AP1 and p27KIP1 (P < .001 and P < .01, respectively). Furthermore, there was a significant relationship between TβR-II expression and p-Smad2 (P < .001). The in vivo correlation of the levels of TβR-II, p12CDK2-AP1, and p27 KIP1 was confirmed in normal and OSCC cell lines. Additionally, in vitro analysis of TGF-β1-treated cells showed that TGF-β1 treatment of normal keratinocytes suppressed cell growth with upregulation of p-Smad2, p12CDK2-AP1, and p21WAF1 expression, whereas there was no effect on OSCC cell lines. These results provide evidence of a link between a disrupted TGF-β-Smad signaling pathway and loss of induction of cell cycle-inhibitory proteins, especially p12CDK2-AP1 in OSCC, which may lead to the resistance of TGF-β1 growth-inhibitory effect on OSCC. Copyright © 2006 Neoplasia Press, Inc. All rights reserved.