曲美替尼对K-ras突变直肠癌细胞恶性行为、耐药蛋白及巨噬细胞极化的作用机制的研究  

Effect of Trimetinib on malignant behavior,drug-resistant protein and macrophage polarization of K-ras mutant rectal cancer cells

作　　者：舒海韵 张汝一[1] 杨远 王新俊 SHU Haiyun;ZHANG Ruyi;YANG Yuan;WANG Xinjun(Guizhou Medical University,Guiyang 550004;Clinical Experiment Research Center,Affiliated Hospital of Guizhou University,China)

机构地区：[1]贵州医科大学,贵州贵阳550004 [2]贵州大学附属医院临床实验研究中心

出　　处：《胃肠病学和肝病学杂志》2023年第3期264-269,共6页Chinese Journal of Gastroenterology and Hepatology

基　　金：国家自然科学基金项目(19NSP045);贵州省自然科技项目(黔科合支撑[2019]2788号)。

摘　　要：目的探讨曲美替尼对K-ras突变直肠癌细胞恶性行为、耐药蛋白及巨噬细胞极化的作用机制。方法取K-ras突变直肠癌细胞HCT116,将其随机分为HCT116组(HC组)、西妥昔单抗+HCT116组(CE组)、低剂量曲美替尼+HCT116组(LT组)、中剂量曲美替尼+HCT116组(MT组)、高剂量曲美替尼+HCT116组(HT组),Transwell实验及划痕实验检测细胞恶性行为,MTT法检测药物敏感性,RT-PCR法检测耐药蛋白表达,免疫印迹法检测巨噬细胞极化相关指标。结果与HC组相比,其余四组细胞侵袭、迁移及GST-π、P-gp、TopoⅡ、CD163表达显著降低(P<0.05),CD40蛋白表达显著升高(P<0.05);与LT组相比,MT组、HT组细胞侵袭、迁移及GST-π、P-gp、TopoⅡ、CD163表达显著降低(P<0.05),CD40蛋白表达显著升高(P<0.05),且HT组比MT组变化明显(P<0.05);HCT116细胞对西妥昔单抗与曲美替尼均敏感,但与西妥昔单抗相比,曲美替尼的IC_(50)明显更低(P<0.05)。结论曲美替尼对K-ras突变直肠癌细胞具有显著疗效,可显著改善其恶性行为,抑制耐药蛋白表达,抑制巨噬细胞M2极化。Objective To investigate the effect of Trimetinib on malignant behavior,drug-resistant protein and macrophage polarization of K-ras mutant rectal cancer cells.Methods Renal K-ras mutant rectal cancer cells HCT116 were taken and randomly divided into HCT116 group(HC group),Cetuximab+HCT116 group(CE group),low-dose Trimetinib+HCT116 group(LT group),medium-dose Trimetinib+HCT116 group(MT group),high-dose Trimetinib+HCT116 group(HT group),cellular malignant behavior was detected by Transwell assay and scratches assay,drug sensitivity was detected by MTT assay,drug-resistant protein expression was detected by RT-PCR,and macrophage polarization related indexes were detected by Western blotting.Results Compared with HC group,cell invasion,migration and the expressions of GST-π,P-gp,TopoⅡand CD163 in other four groups were significantly decreased(P<0.05),while the expression of CD40 protein was significantly increased(P<0.05).Compared with LT group,cell invasion,migration and the expressions of GST-π,P-gp,TopoⅡand CD163 in MT group and HT group were significantly decreased(P<0.05),while the expression of CD40 protein was significantly increased(P<0.05),and the changes in HT group were more obvious than those in MT group(P<0.05).HCT116 cells were sensitive to both Cetuximab and Trimetinib,but the IC 50 of Trimetinib was significantly lower than that of Cetuximab(P<0.05).Conclusion Trimetinib has a significant effect on K-ras mutant rectal cancer cells,which can significantly improve the malignant behavior,inhibit the expression of drug-resistant protein,and inhibit the M2 polarization of macrophages.

关 键 词：曲美替尼 K-ras突变直肠癌细胞 恶性行为 耐药蛋白 巨噬细胞极化 

分 类 号：R735.3[医药卫生—肿瘤]