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Open Access Research article

Gene and functional up-regulation of the BCRP/ABCG2 transporter in hepatocellular carcinoma

Caecilia HC Sukowati1*, Natalia Rosso1, Devis Pascut1, Beatrice Anfuso1, Giuliano Torre2, Paola Francalanci2, Lory S Crocè13 and Claudio Tiribelli13

Author Affiliations

1 Centro Studi Fegato, Fondazione Italiana Fegato, Bld Q AREA Science Park Basovizza, Trieste, Italy

2 Ospedale Pediatrico Bambino Gesù, Rome, 00100, Italy

3 Department of Medicine, University of Trieste, Trieste, 34100, Italy

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BMC Gastroenterology 2012, 12:160  doi:10.1186/1471-230X-12-160

Published: 15 November 2012

Abstract

Background

The Breast Cancer Resistance Protein (BCRP/ABCG2) is one member of ABC transporters proteins super family responsible of drug resistance. Since data on ABCG2 expression in liver malignances are scanty, here we report the expression of ABCG2 in adult human hepatocellular carcinoma (HCC) in both in vivo and in vitro models with different degree of malignancy.

Methods

In cell lines derived from human hepatocellular carcinoma, ABCG2 gene expression was assessed by reverse transcription quantitative real time PCR and function by Hoechst 33342 efflux assay; protein content was assessed by SDS-PAGE Western blot.

Results

ABCG2 expression was found to be highest in the most undifferentiated cell lines, and this was related with a higher functional activity. ABCG2 expression was sensitive to antineoplastic drugs since exposure to 5 μM doxorubicin for 24 hours resulted in significant up-regulations of ABCG2 in all cell lines, particularly in those lines with low basal ABCG2 expression (p<0.01). The gene expression was also investigated in 51 adult liver tissues with HCC and related cirrhosis; normal liver tissue was used as control. ABCG2 gene expression was higher in HCC than both cirrhotic paired tissue and normal tissue. This up-regulation was greater (p<0.05) in pathological poorly differentiated grade G3/G4 than in well-differentiated G1/G2 HCC.

Conclusions

Our results suggest a correlation of ABCG2 gene expression and differentiation stage both in human and HCC derived cell lines. The rapid up-regulation of ABCG2 to exposure to doxorubicin emphasizes the importance of this transporter in accounting for drug resistance in liver tumors.

Keywords:
Liver cancer; Drug resistance; Gene expression; Doxorubicin