Expression of multidrug resistance-associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin
Expression of multidrug resistance-associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin
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DOI：
10.1111/j.1478-3231.2008.01889.x
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发表时间：
2008-11-01
影响因子：
6.7
通讯作者：
Roskams, Tania
中科院分区：
文献类型：
--
作者：
Borght, Sara Vander;Komuta, Mina;Roskams, Tania
背景：肝细胞癌（HCC）由于多药耐药（MDR）而对化疗反应较差。最近的研究表明，部分肝癌可能是祖细胞起源的。由于一些MDR转运蛋白[多药耐药相关蛋白1（MRP 1）、MDR 1、MRP 3和乳腺癌耐药蛋白（BCRP）]在肝祖细胞（HPC）中表达，因此HCC中的表达可能反映了祖细胞来源，并为肿瘤细胞提供了MDR表型。方法：对139例肝癌组织中转运蛋白基因的转录谱进行了分析。此外，我们对一组独立的23例HCC和周围肝脏进行了实时逆转录-聚合酶链反应和免疫组织化学，检测MRP 1、MRP 3、MDR 1、BCRP和胆汁/HPC标记物角蛋白7和/或角蛋白19（K7/K19）。结果：微阵列分析显示，MRP 1是唯一的转运蛋白，与周围组织相比，在HCC中的mRNA水平增加。MRP 1 mRNA水平在生存率差的HCC和HCC的“成肝细胞亚型”（被认为来源于HPC）中显著较高。在23例独立肝细胞癌中的11例中，我们发现MRP 1的弥漫性蛋白表达与正常（周围）肝细胞中观察到的阴性肝细胞表达相比。MRP 1在K19（+）非肿瘤性HPC和K19（+）肿瘤细胞中表达。此外，MRP 3和BCRP在K7/K19（+）肿瘤细胞中表达。MRP 1在低分化HCC、大肿瘤（> 7 cm）和微血管浸润性肿瘤中表达较高。结论：在两个独立的HCC系列中，MRP 1与K19 mRNA和蛋白表达相关。此外，MRP 1与MRP 3和BCRP一起与肿瘤中的K7/K19共定位。因此，MRP 1表达可能反映了这一亚组HCC的HPC起源，并可能导致侵袭性肿瘤表型。
Background: Hepatocellular carcinoma (HCC) responds poorly to chemotherapy owing to multidrug resistance (MDR). Recent studies showed that part of HCC could be of progenitor cell origin. Because some MDR-conferring transporters [multidrug resistance-associated protein 1 (MRP1), MDR1, MRP3 and breast cancer resistance protein (BCRP)] are expressed in hepatic progenitor cells (HPCs), expression in HCC might reflect a progenitor cell origin and provide the tumour cells with a MDR phenotype. Methods: The transcriptional profile of transporter genes was assessed in 139 HCCs earlier subjected to global gene expression analysis. In addition, we performed real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry for MRP1, MRP3, MDR1, BCRP and biliary/HPC markers keratin 7 and/or keratin 19 (K7/K19) on an independent set of 23 HCCs and surrounding liver. Results: Micro-array analysis showed that MRP1 was the only transporter with increased mRNA levels in HCC compared with the surrounding tissue. MRP1 mRNA levels were significantly higher in HCCs with poor survival and the 'hepatoblast subtype' of HCC, thought to be derived from HPCs. In 11 of 23 HCCs of the independent set, we found a diffuse protein expression of MRP1 compared with negative hepatocytic expression observed in normal (surrounding) hepatocytes. MRP1 was expressed in K19(+) non-neoplastic HPCs and K19(+) tumour cells. In addition, MRP3 and BCRP were expressed in K7/K19(+) tumour cells. MRP1 expression was high in poorly differentiated HCCs, large tumours (> 7 cm) and microvascular invasive tumours. Conclusions: MRP1 correlated with K19 mRNA and protein expression in two independent series of HCC. In addition, MRP1 was, together with MRP3 and BCRP, colocalized with K7/K19 in the tumour. Therefore, MRP1 expression could be a reflection of the HPC origin of this subgroup of HCCs and may result in an aggressive tumour phenotype.