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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zollner, G; Wagner, M; Fickert, P; Silbert, D; Fuchsbichler, A; Zatloukal, K; Denk, H; Trauner, M.
Hepatobiliary transporter expression in human hepatocellular carcinoma.
Liver Int. 2005; 25(2):367-379
Doi: 10.1111/j.1478-3231.2005.01033.x
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PubMed
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- Führende Autor*innen der Med Uni Graz
- Trauner Michael
- Zollner Gernot
- Co-Autor*innen der Med Uni Graz
- Denk Helmut
- Fickert Peter
- Silbert-Wagner Dagmar
- Wagner Martin
- Zatloukal Kurt
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- Abstract:
- 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. 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. 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. 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. Copyright Blackwell Munksgaard 2005
- Find related publications in this database (using NLM MeSH Indexing)
- ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - metabolism
- Base Sequence -
- Biopsy, Needle -
- Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - pathology
- Case-Control Studies -
- Drug Resistance, Multiple -
- Female -
- Gene Expression Regulation, Neoplastic -
- Humans -
- Immunohistochemistry -
- Liver Neoplasms - drug therapy Liver Neoplasms - pathology
- Male -
- Molecular Sequence Data -
- Neoplasm Staging -
- P-Glycoproteins - genetics P-Glycoproteins - metabolism
- Probability -
- Prognosis -
- RNA, Neoplasm - analysis
- Reverse Transcriptase Polymerase Chain Reaction -
- Risk Assessment -
- Sensitivity and Specificity -
- Tissue Culture Techniques -
- Tumor Markers, Biological - analysis
- Find related publications in this database (Keywords)
- bile salt-coupled drugs
- chemoresistance
- multidrug resistance