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BMC Cancer. 2012; 12: 109.
Published online Mar 22, 2012. doi:  10.1186/1471-2407-12-109
PMCID: PMC3323414
Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance
Michael Heise,#2 Anja Lautem,#2 Johanna Knapstein,1 Jörn M Schattenberg,1 Maria Hoppe-Lotichius,2 Daniel Foltys,2 Nina Weiler,2 Anca Zimmermann,1 Arno Schad,4 Dirk Gründemann,3 Gerd Otto,2 Peter R Galle,1 Marcus Schuchmann,1 and Tim Zimmermanncorresponding author1
11st Department of Internal Medicine, Johannes Gutenberg University Mainz, Germany
2Department of Hepatobiliary and Transplantation Surgery, Johannes Gutenberg University Mainz, Germany
3Department of Pharmacology, University of Cologne, Germany
4Institute of Pathology, Johannes Gutenberg University Mainz, Germany
corresponding authorCorresponding author.
#Contributed equally.
Michael Heise: michael.heise/at/unimedizin-mainz.de; Anja Lautem: anja.lautem/at/unimedizin-mainz.de; Johanna Knapstein: johanna.knapstein/at/unimedizin-mainz.de; Jörn M Schattenberg: schatten/at/uni-mainz.de; Maria Hoppe-Lotichius: maria.hoppe-lotichius/at/unimedizin-mainz.de; Daniel Foltys: foltys/at/transplantation.klinik.uni-mainz.de; Nina Weiler: nina.weiler/at/unimedizin-mainz.de; Anca Zimmermann: zimmeran/at/uni-mainz.de; Arno Schad: schad/at/pathologie.klinik.uni-mainz.de; Dirk Gründemann: dirk.gruendemann/at/uni-koeln.de; Gerd Otto: otto/at/transplantation.klinik.uni-mainz.de; Peter R Galle: galle/at/uni-mainz.de; Marcus Schuchmann: schuchm/at/uni-mainz.de; Tim Zimmermann: tim.zimmermann/at/unimedizin-mainz.de
Received August 8, 2011; Accepted March 22, 2012.
Abstract
Background
Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).
Methods
OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs.
Results
Real time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p ≤ 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression.
In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC.
Conclusion
The downregulation of OCT1 is associated with tumor progression and a worse patient survival.
Keywords: OCT1, OCT3, SLC22A1, SLC22A3, Hepatocellular carcinoma, HCC
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