ABC 转运蛋白在肝细胞癌中的表达及意义*

于树娜; 蒋吉英; 赵世福; 魏德全; 丁 洁; 王宝松; 姜栋栋①

doi:10.3969/j.issn.1000-8179.2010.04.004

摘要: 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% 、79.41% 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。

Abstract: 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 19cases of paraneoplastic hepatic tissues. Results: The expression of MDR 1, MRP 1 and BCRP mRNA (messenger ribonucleic acid) was 1.15± 0.24, 0.64± 0.33, and 1.07± 0.32in hepatocellular carcinoma and 0.36± 0.14, 0.19± 0.06, and 0.31± 0.09in paraneoplastic hepatic tissues. The expression of MDR 1, MRP 1 and BCRP mRNA was 1.38± 0.26, 0.73± 0.35, and 1.34± 0.21in poorly differentiated hepatocellular carcinoma and 0.74± 0.32, 0.30± 0.11, and 0.45± 0.13in well differentiated hepatic tissues. The immunohistochemical positive substance was detected in the plasma membrane and cytoplasm. The positive rates of P-gp, MRP 1 and BCRP were 82.35% , 58.82% , and 79.41% in hepatocellular carcinoma and 42.11% ,26.32% , and36.84% in paraneoplastic hepatic tissues, respectively. The positive rates of P-gp, MRP 1 and BCRP were 100 .00% ,81.25% , and100 .00% in poorly differentiated hepatocellular carcinoma and 66.67%,38.89%, and61.11% 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/MDR 1, MRP 1 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/MDR 1,MRP1 and BCRP. MRP1 and BCRP may be targets for reversing multidrug resistance.

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