ABC转运蛋白在肝细胞癌中的表达及意义

Expression and Significance of ATP-Binding Cassette Proteins in Hepatocellular Carcinoma

目的:探讨P-gp、MRP1、BCRP等ABC转运蛋白在肝细胞癌中的表达及其与临床病理特征的关系。方法:应用RT-PCR和免疫组织化学方法检测P-gp/MDR1、MRP1、BCRP等mRNA及蛋白在34例的肝细胞癌、19例癌旁肝组织中的表达。结果:MDR1、MRP1、BCRP等mRNA在肝癌组的相对表达水平分别为1.15±0.24、0.64±0.33、1.07±0.32,在癌旁肝组织组的相对表达水平分别为0.36±0.14、0.19±0.06、0.31±0.09。MDR1、MRP1、BCRP在肝细胞癌中低分化组(Ⅲ、Ⅳ级)为1.38±0.26、0.73±0.35、1.34±0.21,在高分化组(Ⅰ、Ⅱ级)分别为0.74±0.32、0.30±0.11、0.45±0.13。P-gp、MRP1、BCRP等的阳性反应产物主要分布于细胞膜和胞浆内;在肝癌组和癌旁肝组织组的阳性表达率分别为82.35%、58.82%、79.4l%和42.11%、26.32%、36.84%。P-gp、MRP1、BCRP在肝细胞癌中低分化组(Ⅲ、Ⅳ级)的阳性表达率分别为100%、81.25%、100%,在高分化组(Ⅰ、Ⅱ级)的阳性表达率分别为66.67%、38.89%、61.11%。RT-PCR及免疫组织化学均显示,P-gp、MDR1、MRP1、BCRP mRNA和蛋白在肝癌组的表达均高于癌旁肝组织组,且在低分化(Ⅲ、Ⅳ级)肝癌组织的表达高于高分化者(Ⅰ、Ⅱ级),差异有统计学意义(P<0.05)。MDR1、MRP1、BCRP之间的表达无线性相关。结论:在肝细胞癌中存在原发性多药耐药现象,且多种耐药机制并存。P-gp、MDR1、MRP1、BCRP等与肝细胞癌的耐药有关,在肝癌组的表达高于癌旁肝组织组,且在肝细胞癌中的表达随着肿瘤分化程度的增高而降低,可作为肝细胞癌多药耐药性作用的靶点。

Objective： To investigate the expression of ATP-Binding Cassette Proteins including P-gp （P-glycoprotein）, MRP1 （multidrug resistance associated protein 1） and BCRP （breast cancer resistance protein） in hepatocellular carcinoma and its relationship with pathological features. Methods： The expression of P-gp/MDR1 （multidrug resistance gene 1）, MRP1 and BCRP in hepatocellular carcinoma was examined by RT-PCR and immunohistochemistry in 34 cases of hepatocellular carcinoma and 19 cases of paraneoplastic hepatic tissues. Results： The expression of MDR1, MRP1 and BCRP mRNA （messenger ribonucleic acid） was 1.15± 0.24, 0.64± 0.33, and 1.07 ± 0.32 in hepatocellular carcinoma and 0.36±0.14, 0.19±0.06, and 0.31±0.09 in paraneoplastic hepatic tissues. The expression of MDR1, MRP1 and BCRP mRNA was 1.38±0.26, 0.73±0.35, and 1.34±0.21 in poorly differentiated hepatocellular carcinoma and 0.74＋0.32, 0.30±0.11, and 0.45±0.13 in well differentiated hepatic tissues. The immunohistochemical positive substance was detected in the plasma membrane and cytoplasm. The positive rates of P-gp, MRP1 and BCRP were 82.35%, 58.82%, and 79.41% in hepatocellular carcinoma and 42.11%, 26.32%, and 36.84% in paraneoplastic hepatic tissues, respectively. The positive rates of P-gp, MRP1 and BCRP were 100.00%, 81.25%, and 100.00% in poorly differentiated hepatocellular carcinoma and 66.67%, 38.89%, and 61.11% in well differentiated hepatic tissues. The expression of three indicies in hepatocellular carcinoma was higher than that in paraneoplastic hepatic tissues （P〈0.05）. The expression of P-gp/MDR1, MRP1 and BCRP in poorly differentiated hepatocellular carcinoma was higher than that in well differentiated hepatic tissues （P〈0.05）. No correlation was found among the three indices. Conclusion： Intrinsic multidrug resistance exsists in hepatocellular carcinoma, with various mechanisms. The multidrug resistance of HCC （hepatic cell carcinoma） is related to P-gp/MDR1, MRP1 and BCRP. MRP1 and BCRP may be targets for reversing multidrug resistance.