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

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.