Smad4蛋白与蛋白激酶在非小细胞肺癌信号传导通路中的作用

The role of Smad4 and MAPK proteins in signal transduction pathway in non-small cell lung cancer

目的探讨Smad4在非小细胞肺癌(NSCLC)中的表达,研究其与有丝分裂激活的蛋白激酶(MAPK)各亚族的关系和临床意义。方法应用Western印迹分析和RT-PCR方法,检测42例手术切除的肺癌标本和正常肺组织中Smad4的表达;应用免疫组化法,检测71例肺癌蜡块标本中Smad4和MAPK的亚族p38、ERK1、JNK1的表达。对各因子进行生存分析,判断对NSCLC预后的影响。结果在肺癌组织中,Smad4蛋白和mRNA的表达均低于正常组织(P<0．05);p38、ERK1和Smad4的表达与病理分期有关(P=0．000;P=0．000;P=0．005);JNK1的表达与肿瘤位置(P= 0．028)和病理分期(P=0．000)有关;Smad4和p38(P=0．000)明显相关。单因素分析显示,Smad4 (P=0．0001)、p38(P=0．0000)、JNK1(P=0．0208)、肿瘤分化(P=0．0059)和病理分期(P=0．0000)与预后相关。多因素分析显示,Smad4(P=0．019)、p38(P=0．044)、肿瘤分化(P=0．003)和病理分期(P=0．020)与预后明显相关。p38阴性而Smad4阳性的肺癌患者预后较好(P=0．000)。结论Smad4的表达在NSCLC的发生发展中可能起重要意义。在NSCLC中,ras-MAPK信号通路、转换生长因子β(TGF-β)／Smad4信号通路的主要蛋白密切相关,p38和ERK1抑制Smad4的表达。Smad4和p38可用于判断NSCLC的预后。

Objective To investigate the expression of Smad4 in non-small cell lung cancer （NSCLC）, its correlation with MAPK （mitogen activated protein kinase） and their clinical significance in NSCLC. Methods Western blotting and RT-PCR were employed to test 42 resected lung cancers and normal lung tissues for the expression of Smad4o Imunohistochemistry was used to detect Smad4 and subtribes of MAPK in 71 paraffin samples. Results The level of protein and mRNA expression of Smad4 in lung cancer tissues were 0.2092 ±0. 1308 and 0. 3986 ±0. 1982, respectively, lower than those in normal tissues （0. 7852 ± 0. 4386 and 1. 1206 ± 0. 6772, P 〈 0.05 ）. The expression of p38, ERK1 and Smad4 was associated with TNM staging （P = 0. 000, 0. 000 and 0.005, respectively） and JNK1 with tumor location（ P = 0.028）and staging （P =0. 000）. There was a correlation between p38 and Smad4 （P =0. 000）. The expression of Smadd （P=0.0001）, p38 （P=0.0000） and JNK1 （P=0.0208）, tumor differentiation （ P= 0. 0059） and staging （P =0. 0000） were significantly correlated with prognosis of NSCLC by univariate analysis. Smad4（ P = 0. 019 ）, p38 （ P = 0. 044 ）, tumor differentiation （ P = 0. 003 ）, and staging （ P = 0.020） were correlated with prognosis tested by multivariable analysis. Taking p38 and Smad4 together, we found that the negative expression of p38 and positive expression of Smad4 were associated with a better prognosis of NSCLC （ P = 0. 000）. Conclusion Smad4 could be of importance for the initiation and development of NSCLC. There is a significant correlation between main proteins of TGF-β/smad4 and those of ras-MAPK signal transduction pathways. The expression of Smad4 is inhibited by p38. Smad4, as well as p38, tumor differentiation and staging can be used as prognostic factors of NSCLC.