Bennett W P, el-Deiry W S, Rush W L, Guinee D G, Freedman A N, Caporaso N E, Welsh J A, Jones R T, Borkowski A, Travis W D, Fleming M V, Trastek V, Pairolero P C, Tazelaar H D, Midthun D, Jett J R, Liotta L A, Harris C C
National Cancer Institute, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 1998 Jun;4(6):1499-506.
p21waf1/cip1 encodes a cyclin-dependent kinase inhibitor that is transcriptionally activated by the p53 tumor suppressor gene, transforming growth factor beta 1 (TGF-beta 1), AP2, and other pathways. Because p21waf1/cip1, p53, and TGF-beta 1 all regulate apoptosis and the cell cycle, we tested the hypothesis that their relative protein levels would correlate with biological features including the survival of non-small cell lung cancer (NSCLC) patients. We conducted an immunohistochemical analysis of p21waf1/cip1 and TGF-beta 1 and identified four patient groups with distinct survival outcomes. Concordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and high TGF-beta 1 expression or low p21waf1/cip1 and low TGF-beta 1 expression) predicted 70% disease-free survival at 2000 days of follow-up. Discordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and low TGF-beta 1 expression or low p21waf1/cip1 and high TGF-beta 1 expression) predicted 35% disease-free survival (P = 0.0003; log-rank test). These survival relationships were not attributable to differences in grade, stage, or p53 status. Although current models do not fully explain these complex interactions, most of these data fit a paradigm whereby TGF-beta 1 regulation determines NSCLC survival. In addition to the survival correlation, we found that high p21waf1/cip1 protein expression correlated with high tumor grade (P = 0.014). There is little evidence that p21waf1/cip1 protein levels accurately predict p53 mutation status in NSCLC; specifically, 20 of 48 (42%) tumors with p53 mutations contained high levels of p21waf1/cip1 protein. These findings indicate that p21waf1/cip1 immunohistochemical analysis may provide useful information concerning the biological properties of NSCLC.
p21waf1/cip1编码一种细胞周期蛋白依赖性激酶抑制剂，它可被p53肿瘤抑制基因、转化生长因子β1（TGF-β1）、AP2及其他信号通路转录激活。由于p21waf1/cip1、p53和TGF-β1均调控细胞凋亡和细胞周期，我们检验了这样一个假设，即它们的相对蛋白水平与包括非小细胞肺癌（NSCLC）患者生存率在内的生物学特征相关。我们对p21waf1/cip1和TGF-β1进行了免疫组化分析，并确定了四个具有不同生存结局的患者组。p21waf1/cip1和TGF-β1表达一致（即p21waf1/cip1高表达且TGF-β1高表达，或p21waf1/cip1低表达且TGF-β1低表达）的患者在随访2000天时的无病生存率预测为70%。p21waf1/cip1和TGF-β1表达不一致（即p21waf1/cip1高表达且TGF-β1低表达，或p21waf1/cip1低表达且TGF-β1高表达）的患者无病生存率预测为35%（P = 0.0003；对数秩检验）。这些生存关系并非归因于分级、分期或p53状态的差异。尽管目前的模型不能完全解释这些复杂的相互作用，但大多数数据符合一种模式，即TGF-β1调控决定NSCLC的生存。除了生存相关性外，我们发现p21waf1/cip1蛋白高表达与肿瘤高分级相关（P = 0.014）。几乎没有证据表明p21waf1/cip1蛋白水平能准确预测NSCLC中的p53突变状态；具体而言，48个（42%）p53突变肿瘤中有20个含有高水平的p21waf1/cip1蛋白。这些发现表明，p21waf1/cip1免疫组化分析可能为NSCLC的生物学特性提供有用信息。
