Hepatobiliary transporter expression in human hepatocellular carcinoma.
OBJECTIVE
Treatment of hepatocellular carcinoma (HCC) is hampered by resistance to chemotherapy, which might be mediated by multidrug resistance P-glycoproteins (MDR P-gps) and MDR-associated proteins (MRPs). The effectiveness of cytostatics could be further impeded by reduced hepatocellular drug uptake into HCCs. Therefore, we aimed to determine P-gp, MRP and organic anion transporting protein OATP2 (SLC21A6) expression in HCC. Furthermore, we investigated expression of the major bile salt uptake system Na(+)/taurocholate cotransporter NTCP (SLC10A1), since bile salt-coupled chemotherapeutics were proposed to increase therapeutic drug enrichment in HCC.


METHODS
mRNA and protein expression and tissue distribution of P-gps, MRPs, OATP2 and NTCP were assessed in HCC and peritumorous non-neoplastic tissue by reverse transcription polymerase chain reaction, Western blotting and immunohistochemistry, respectively.


RESULTS
Expression of P-gps (multidrug export pump MDR1 (ABCB1), phospholipid flippase MDR3 (ABCB4), sister of P-glycoprotein SPGP (ABCB11)) and basolateral MRP homologue MRP3 (ABCC3) showed a trend for decreased levels in HCC but was highly variable among individual tumors. In contrast, canalicular conjugate export pump MRP2 (ABCC2) expression was generally maintained or even showed a trend towards increased levels. NTCP and OATP2 expression was markedly reduced in most HCCs (P < 0.05). Expression of the genuine drug transporter, the concentrative nucleoside transporter (CNT1), was highly variable and showed a trend for reduced levels in HCC.


CONCLUSIONS
MRP2 seems to be the major candidate transporter involved in chemoresistance and reduced expression of OATP2 may further contribute to low drug accumulation in HCCs. Overexpression of drug exporters is not a general feature of HCC but could account for chemoresistance of individual cases. Since expression of uptake systems is generally reduced in HCC, bile salt-coupled therapeutics may not represent a suitable strategy to overcome insufficient drug enrichment.
Zollner
Gernot
G
Division of Gastroenterology and Hepatology, Department of Medicine, Medical University,Auenbruggerplatz 15, A-8036 Graz, Austria.
Wagner
Martin
M
Fickert
Peter
P
Silbert
Dagmar
D
Fuchsbichler
Andrea
A
Zatloukal
Kurt
K
Denk
Helmut
H
Trauner
Michael
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D016022:Case-Control Studies; D018432:Drug Resistance, Multiple; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008969:Molecular Sequence Data; D000089762:Multidrug Resistance-Associated Protein 2; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D046509:Tissue Culture Techniques
C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D014408:Biomarkers, Tumor; D000089762:Multidrug Resistance-Associated Protein 2; D012334:RNA, Neoplasm