Abstract
BackgroundOrganic cation transporters (OCTs) determine not only physiological processes but are also involved in the cellular uptake of anticancer agents. Based on microarray analyses in hepatocellular carcinoma (HCC), SLC22A1/OCT1 mRNA seems to be downregulated, but systematic protein expression data are currently missing. Moreover, the underlying molecular mechanisms responsible for altered SLC22A1 expression in HCC are not fully understood. Therefore, we investigated the role of DNA methylation in the transcriptional regulation of the family members SLC22A1/OCT1, SLC22A2/OCT2 and SLC22A3/OCT3 in HCC.MethodsSemiquantitative immunohistochemistry of SLC22A1 protein expression was performed in paired HCC and histological normal adjacent liver tissues (n = 71) using tissue microarray analyses, and the results were correlated with clinicopathological features. DNA methylation, quantified by MALDI-TOF mass spectrometry and gene expression of SLC22A1, SLC22A2 and SLC22A3 were investigated using fresh-frozen HCC (n = 22) and non-tumor adjacent liver tissues as well as histologically normal liver samples (n = 120) from a large-scale liverbank.ResultsBased on tissue microarray analyses, we observed a significant downregulation of SLC22A1 protein expression in HCC compared to normal adjacent tissue (P < 0.0001). SLC22A1 expression was significantly inverse correlated with expression of the proliferation marker MIB1/Ki-67 (rs = -0.464, P < 0.0001). DNA methylation of SLC22A1 was significantly higher in HCC compared with non-tumor adjacent liver tissue and was lowest in histologically normal liver tissue. Methylation levels for SLC22A1 in combination with RASSF1A resulted in a specificity of > 90% and a sensitivity of 82% for discriminating HCC and tumor-free liver tissue.ConclusionsDNA methylation of SLC22A1 is associated with downregulation of SLC22A1 in HCC and might be a new biomarker for HCC diagnosis and prognosis. Moreover, targeting SLC22A1 methylation by demethylating agents may offer a novel strategy for anticancer therapy of HCC.
Highlights
Organic cation transporters (OCTs) determine physiological processes but are involved in the cellular uptake of anticancer agents
Expression profiling of SLC22A1, SLC22A2, and SLC22A3 in normal and tumor tissue A comprehensive analysis using cDNAs from 381 human tissue samples (Table S1 in Additional file 1) from 20 different tissues revealed that SLC22A1 mRNA is expressed most prominently in normal liver and expressed at significantly lower levels in hepatocellular carcinoma (HCC) tissues (P = 0.029; Figure 1A)
SLC22A1 protein expression is significantly decreased in HCC compared with tumor-free adjacent liver tissue
Summary
Organic cation transporters (OCTs) determine physiological processes but are involved in the cellular uptake of anticancer agents. Based on microarray analyses in hepatocellular carcinoma (HCC), SLC22A1/OCT1 mRNA seems to be downregulated, but systematic protein expression data are currently missing. The underlying molecular mechanisms responsible for altered SLC22A1 expression in HCC are not fully understood. Therapeutic options include sorafenib, as first effective systemic treatment against HCC, as well as the expression of these transporters is suggested to be a significant determinant of physiological functions in different organs [3,4,5]. There is already evidence that OCTs are differentially expressed in tumor tissues, and based on microarray data, SLC22A1 mRNA expression is downregulated in HCC [9,10,11]. The underlying mechanisms responsible for altered expression of SLC22A1 in HCC compared with normal liver are poorly understood
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