Vander Borght Sara, Komuta Mina, Libbrecht Louis, Katoonizadeh Aezam, Aerts Raymond, Dymarkowski Steven, Verslype Chris, Nevens Frederik, Roskams Tania
Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium.
Liver Int. 2008 Dec;28(10):1370-80. doi: 10.1111/j.1478-3231.2008.01889.x.
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.
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.
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.
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.
由于多药耐药（MDR），肝细胞癌（HCC）对化疗反应不佳。最近的研究表明，部分HCC可能起源于祖细胞。因为一些赋予MDR的转运蛋白[多药耐药相关蛋白1（MRP1）、MDR1、MRP3和乳腺癌耐药蛋白（BCRP）]在肝祖细胞（HPC）中表达，所以在HCC中的表达可能反映了祖细胞起源，并赋予肿瘤细胞MDR表型。
在先前进行过全基因表达分析的139例HCC中评估转运蛋白基因的转录谱。此外，我们对另外23例HCC及其周围肝脏组织进行了实时逆转录聚合酶链反应，并对MRP1、MRP3、MDR1、BCRP以及胆管/肝祖细胞标志物角蛋白7和/或角蛋白19（K7/K19）进行了免疫组织化学检测。
微阵列分析显示，与周围组织相比，MRP1是HCC中唯一mRNA水平升高的转运蛋白。在生存期短的HCC以及被认为起源于HPC的HCC“肝母细胞亚型”中，MRP1 mRNA水平显著更高。在独立队列的23例HCC中，有11例发现MRP1呈弥漫性蛋白表达，而在正常（周围）肝细胞中观察到的是阴性肝细胞表达。MRP1在K19（+）非肿瘤性HPC和K19（+）肿瘤细胞中表达。此外，MRP3和BCRP在K7/K19（+）肿瘤细胞中表达。MRP1在低分化HCC、大肿瘤（>7 cm）和微血管侵犯性肿瘤中表达较高。
在两个独立的HCC队列中，MRP1与K19 mRNA和蛋白表达相关。此外，MRP1与MRP3和BCRP一起在肿瘤中与K7/K19共定位。因此，MRP1的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。
