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Anja Lautem,
Michael Heise,
Andreas Gräsel,
Maria Hoppe-Lotichius,
Nina Weiler,
Daniel Foltys,
Johanna Knapstein,
Jörn M Schattenberg,
Arno Schad,
Anca Zimmermann,
Gerd Otto,
Hauke Lang,
Peter R Galle,
Marcus Schuchmann,
Tim Zimmermann
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ABSTRACT: Cholangiocellular carcinoma (CCA) is a primary hepatic malignancy derived from cholangiocytes. The prognosis for CCA patients is very poor and conventional chemotherapy has been proven ineffective in improving long‑term patient survival rates. Organic cation transporters (OCTs) mediate the transport of a broad spectrum of endogenous substrates and the detoxification of xenobiotics. Moreover, OCTs are considered responsible for the responsiveness towards platinum‑based chemotherapies. Currently, there are no data available regarding the role of OCTs in CCA. Therefore, the aim of this study was to investigate the expression of OCT1 and OCT3 in CCA and the corresponding non-neoplastic tumor‑surrounding tissue (TST). OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human CCA by real-time PCR (n=27). Protein expression was determined by western blot analysis and immunohistochemistry. Data were correlated with the clinicopathological parameters of CCA. Real-time PCR demonstrated a downregulation of the expression of SLC22A1 and SLC22A3 in CCA, compared to that in TST (p<0.001). A low SLC22A1 expression was associated with a worse patient survival (p<0.05). The downregulation of SLC22A1 was significantly associated with advanced CCA stages, since tumors with a low SLC22A1 mRNA expression presented with larger tumor diameters (p=0.02). There were no significant differences in tumor characteristics or patient survival in relation to the level of SLC22A3 expression. Western blot analysis and immunohistochemistry confirmed the downregulation of OCT1 and OCT3 protein levels in cancerous tissue compared to those in TST. In conclusion, the downregulation of OCT1 is associated with tumor progression and worse overall patient survival rates.
International Journal of Oncology 04/2013; 42(4):1297-304. · 2.40 Impact Factor
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Michael Heise, Anja Lautem,
Johanna Knapstein,
Jörn M Schattenberg,
Maria Hoppe-Lotichius,
Daniel Foltys,
Nina Weiler,
Anca Zimmermann,
Arno Schad,
Dirk Gründemann,
Gerd Otto,
Peter R Galle,
Marcus Schuchmann,
Tim Zimmermann
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ABSTRACT: 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).
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.
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.
The downregulation of OCT1 is associated with tumor progression and a worse patient survival.
BMC Cancer 03/2012; 12:109. · 3.01 Impact Factor
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Tim Zimmermann,
Maria Hoppe-Lotichius,
Andreas Körner, Anja Lautem,
Michael Heise,
Daniel Foltys,
Nina Weiler,
Stefan Biesterfeld,
Irene Schmidtmann,
Peter R Galle,
Gerd Otto,
Marcus Schuchmann
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ABSTRACT: CYP2D6 is part of the cytochrome P450 system, which catalyzes biotransformation of endogenous substrates and xenobiotics. Approximately 10% of the Caucasian population has two null alleles, resulting in a poor metabolizer (PM) status. Mostly, allele four (CYP2D6*4) is responsible for the PM status, which is suspected to be associated with an accelerated fibrosis progression (FP). The aim of the present study was to analyze the role of the CYP2D6*4 genotype for FP after liver transplantation (LT). Genotypes were determined in liver biopsies (donor) and peripheral blood (recipient) by fluorescence resonance energy transfer. Data were correlated with clinical variables and risk factors for fibrosis. We analyzed 517 LTs performed between 1997 and 2009. Overall donor and recipient allele frequencies were comparable (18.0%, 20.5%; P = 0.43). The donor genotype did not correlate with FP. In contrast, recipients carrying CYP2D6*4, showed a significant higher risk for an accelerated FP (P = 0.011) in HCV positive (P = 0.038) and HCV negative patients (P = 0.033). Results were confirmed by multivariate analysis (Hazard ratio 1.65; P = 0.001). The CYP2D6*4-associated PM status of the donor liver seems to have no influence on FP after LT. Recipients, carrying the allele, have an elevated risk for an accelerated FP.
Transplant International 07/2011; 24(11):1059-67. · 2.92 Impact Factor
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ABSTRACT: It has been shown that certain chemokine receptor polymorphisms may correspond to certain complications after organ transplantation. Ischemic-type biliary lesion (ITBL) encounters for major morbidity and mortality in liver transplant recipients. So far, the exact cause for ITBL remains unclear. Certain risk factors for the development of ITBL like donor age and cold ischemic time are well described. In a previous study, a 32-nucleotide deletion of the chemokine receptor-5Delta32 (CCR-5Delta32) was strongly associated with the incidence of ITBL in adult liver transplantation. This study re-evaluates the association of CCR-5Delta32 gene polymorphism and the incidence of ITBL. 169 patients were included into this retrospective analysis. 134 patients were homozygous for wild-type CCR-5, 33 patients heterozygous, and 2 patients were homozygous for CCR-5Delta32 mutation. There were no major differences in donor or recipients demographics. No association was found between CCR-5Delta32 mutation and the development of ITBL. We conclude that CCR-5Delta32 is no risk factor for the development of ITBL in our patient cohort.
Journal of Transplantation 01/2009; 2009:436515.
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ABSTRACT: Chemokine receptor 5 (CCR-5) plays a central role in allograft rejection. CCR-5Delta32 mutation results in a non-functioning receptor. Homozygous CCR-5Delta32 patients show a significantly improved kidney graft survival rate compared to CCR-5 wild-type patients. Similar correlations between the CCR-5Delta32 genotype and acute rejection or graft survival rate were shown for heart, lung and islet cell transplantation.
The aim of this study was to examine CCR-5Delta32 and acute rejection after liver transplantation (OLT). 158 OLT patients were genotyped. Data of grafts and patients were collected prospectively into a transplant database.
There were no significant differences between groups regarding patient, donor or graft variables. CCR-5 wild-type patients had explicitly more acute rejection episodes (p=0.086) than patients with the heterozygous or homozygous Delta32-mutation. Homozygous Delta32 patients had no acute rejection episodes. 12.5% of heterozygous patients had one acute rejection episode as opposed to 30.6% of wild-type patients. Only wild-type patients experienced more than one rejection episode.
Patients with the Delta32-mutation might be candidates for a minimized immunosuppressive therapy. CCR-5 could be relevant as a target for a new therapeutic approach.
Annals of transplantation: quarterly of the Polish Transplantation Society 14(3):36-44. · 2.02 Impact Factor
