【摘要】 目的探明新近发现的Wnt信号通路的小分子抑制剂IWR-1-endo是否会对三阴性乳腺癌细胞系MDA-MB-231以及该细胞系的裸鼠荷瘤模型的生长产生抑制作用及其机制。方法应用不同浓度的IWR-1-endo处理MDA-MB-231细胞并计算细胞增殖抑制率。建立裸鼠荷瘤模型并且每2天1次腹腔注射IWR-1-endo溶液0.1mL/10g,同时每4天1次测量瘤体长径和短径、计算肿瘤体积。4周后,处死小鼠、收集肿瘤组织、测量并计算体积抑瘤率和瘤重抑瘤率。将肿瘤组织制成石蜡切片,进行Ki-67染色及TUNEL染色,以计算增殖指数和凋亡指数。另应用western blot检测肿瘤细胞和组织中Axin 1、Axin 2、β-catenin和p-β-catenin蛋白的表达。结果 IWR-1-endo可以明显抑制MDA-MB-231细胞的生长,其抑制作用呈浓度依赖型,IC50值为180nmol/L。IWR-1-endo的体积抑瘤率为42.2%,瘤重抑瘤率为44.6%。与对照组比较,IWR-1-endo组凋亡指数上升,差异有统计学意义,而增殖指数差异无统计学意义。western blot检测结果显示细胞及组织中Axin 1和Axin 2表达量明显上升,β-catenin明显下降,而p-β-catenin上升。结论 IWR-1-endo可以通过稳定化Axin而抑制Wnt信号通路,实现对三阴性乳腺癌细胞系及裸鼠荷瘤模型生长的抑制。更多还原

【Abstract】 Objective To investigate whether IWR-1-endo,a newly discovered small molecule inhibitor of Wnt signaling pathway,can suppress the proliferation of triple negative breast cancer cells MDA-MB-231 and nude mice tumor-bearing model and its relative potential mechanism.Methods MDA-MB-231 cells were treated by different concentrations of IWR-1-endo,and the cellular proliferation inhibition rate was calculated.The nude mice tumor-bearing model was constructed by intraperitoneal injection of IWR-1-endo(0.1mL/10 g,once per 2d).The long and short diameters of tumor were measured once every 4d,in order to calculate the tumor volume.Mice were sacrificed after 4weeks to collect tumor tissue for measuring and calculating the suppression rate of volume and weight.The tumor tissue was made into the paraffin sections for conducting Ki-67 staining and TUNEL staining.The proliferative index and apoptotic index were calculated.The expression of Axin 1,Axin 2,β-catenin and p-β-catenin protein was detected by Western blot.Results IWR-1-endo could obviously inhibit the growth of MDA-MB-231 cells in a concentration-dependent manor(IC50value was 180nmol/L).The tumor volume suppression rate of IWR-1-endo was 42.2% and its tumor weight suppression rate was 46.6%.Compared with the control group,the apoptotic index in the IWR-1-endo group was significantly increased,the difference was statistically significant,while the difference of proliferative index had no statistical significance.The Western blot results showed that the expression amount of Axin 1and Axin 2in the cells and tissues was significantly increased,theβ-catenin expression was obviously decreased,while theβ-catenin level was reduced and the p-β-catenin level was increased.Conclusion IWR-1-endo can inhibit the Wnt signal pathway by stabilizing Axin,and realize the inhibition on TNBC cell line and growth of nude mice tumor-bearing model.更多还原