Peng Hui, Shintani Satoru, Kim Yong, Wong David T
Dental Research Institute, School of Dentistry, University of California-Los Angeles, Los Angeles, CA 90095, USA.
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.
我们检测了125例人类口腔鳞状细胞癌（OSCC）中转化生长因子β1（TGF-β1）、转化生长因子βⅠ型受体（TβR-Ⅰ）、转化生长因子βⅡ型受体（TβR-Ⅱ）、p12（周期蛋白依赖性激酶2相关蛋白1，CDK2-AP1）、p21（野生型p53激活片段1，WAF1）、p27（激酶抑制蛋白1，KIP1）、Smad2和磷酸化Smad2（p-Smad2）之间的相关性，以验证以下假说：对TGF-β1诱导的生长抑制产生抗性是由于p12（CDK2-AP1）减少或缺失导致其信号通路中断所致。随着疾病侵袭性增加，OSCC中TβR-Ⅱ的免疫反应性降低；然而，未观察到TβR-Ⅰ和TGF-β1有差异。TβR-Ⅱ的表达与p12（CDK2-AP1）和p27（KIP1）显著相关（分别为P <.001和P <.01）。此外，TβR-Ⅱ表达与p-Smad2之间存在显著关系（P <.001）。在正常和OSCC细胞系中证实了TβR-Ⅱ、p12（CDK2-AP1）和p27（KIP1）水平的体内相关性。此外，对TGF-β1处理细胞的体外分析表明，TGF-β1处理正常角质形成细胞可抑制细胞生长，并上调p-Smad2、p12（CDK2-AP1）和p21（WAF1）的表达，而对OSCC细胞系无影响。这些结果证明了TGF-β-Smad信号通路中断与细胞周期抑制蛋白诱导缺失之间存在联系，尤其是OSCC中的p12（CDK2-AP1），这可能导致OSCC对TGF-β1生长抑制作用产生抗性。
