氨基末端激酶参与胃癌顺铂耐药机制的研究  

Study on the mechanism of DDP-resistance mediated by phosphate JNK in gastric cancer

作　　者：李大卫[1] 彭志海[1] 李真真[2] 张艳红[2] 赵勉之[2] 吴晴[1] 

机构地区：[1]上海交通大学附属第一人民医院普通外科,200080 [2]上海交通大学附属第一人民医院肿瘤科,200080

出　　处：《中华胃肠外科杂志》2008年第2期159-162,共4页Chinese Journal of Gastrointestinal Surgery

基　　金：上海市自然科学基金（03ZR14077）

摘　　要：目的研究氨基末端激酶（p-JNK）参与胃癌SGC7901／DDP细胞株顺铂耐药的机制。方法应用JNK通路抑制剂SP600125抑制p-JNK表达，通过四氮唑盐还原法（MTY）检测药物敏感性；流式细胞术分析细胞凋亡率；Western印迹检测p-JNK和耐药蛋白P-糖蛋白（P—glycoprotein，P-gp）在敏感株SGC7901和耐药株SGC7901／DDP中的表达变化。免疫组织化学方法检测含有168例胃癌和27例正常胃的组织芯片中p-JNK和P—gp的表达及分析其关系。结果SP600125抑制p-JNK表达后．敏感株SGC7901和耐药株SGC7901／DDP的药物敏感性和细胞凋亡率增加（P〈0．01）；耐药蛋白P—gp表达水平明显减低（0．21±0．01和0．77±0．05比0．06±0．01和0．52±0．06；P〈0．01）。p-JNK和P—gp在胃癌组织中的表达分别为45．8％和51．8％，均显著高于正常胃组织中的7．4％和18．5％（P〈0．01）。p-JNK和P-gp的表达呈正相关（P〈0．01）。结论p-JNK通过调节P—gD表达及抗凋亡信号通路参与胃癌顺铂耐药．可成为逆转耐药的新的靶点。Objective To investigate the mechanism of DDP-resistance in gastric cancer cell line SGC7901/DDP mediated by phosphate（p）-JNK. Methods The p-JNK expression was blocked by the JNK inhibitor SP600125. The drug sensitivity was detected by MTT. Cell apoptosis rate was measured by flow cytometry. The expression of p-JNK and P-glycoprotein （P-gp） was examined by Western blot. The expression of both proteins were detected in a tissue microarray containing 168 spots of cancer tissue and 27 spots of normal gastric tissue by SP immunohistochemistry. Pearson method was used to analyze the correlation between p-JNK and P-gp. Results The drug sensitivity and cell apoptosis rate significantly increased （P〈0.01）, and the protein expression levels of p-JNK and P-glycoprotein were down-regulated after the inhibition of p-JNK by SP600125 in both SGC7901 （p- JNK： 1.17±0.03 vs 0.38±0.071, P-gp： 0.21±0.01 vs 0,06±0.01） and SGC7901/DDP （p-JNK： 2.56±0.14 vs 1.02±0.12, P-gp： 0.77±0.05 vs 0.52±0.06 ）cells（all P〈0.01）. The protein expression rates of p-JNK and P-glycoprotein were 45.8% and 51.8% respectively in gastric cancer tissue, which were significantly higher than those in nomal gastric tissue 7.4% a.nd 18.5% （P〈0.01）. The correlation of protein expression of p-JNK and P-gp was positive （P〈0.01）. Conclusion JNK anti-apoptosis pathway with the regulation of P-gp expression plays an important role in the DDP-resistance of gastric cancer, which may be a novel target for reversing multidrug resistance.

关 键 词：胃肿瘤 多药耐药 免疫组织化学 P糖蛋白 氨基末端激酶 

分 类 号：R735.2[医药卫生—肿瘤]