DNA methylation is associated with downregulation of the organic cation transporter OCT1 SLC22A1 in human hepatocellular carcinomaReportar como inadecuado

DNA methylation is associated with downregulation of the organic cation transporter OCT1 SLC22A1 in human hepatocellular carcinoma - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Genome Medicine

, 3:82

First Online: 23 December 2011Received: 13 October 2011Revised: 08 November 2011Accepted: 23 December 2011


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.

AbbreviationsHCChepatocellular carcinoma

MALDI-TOF MSmatrix-assisted laser desorption-ionization time-of-flight mass spectrometry

OCTorganic cation transporter

PCRpolymerase chain reaction

SLCsolute carrier

TMAtissue microarray

UTRuntranslated region.

Electronic supplementary materialThe online version of this article doi:10.1186-gm298 contains supplementary material, which is available to authorized users.

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Autor: Elke Schaeffeler - Claus Hellerbrand - Anne T Nies - Stefan Winter - Stephan Kruck - Ute Hofmann - Heiko van der Kuip - Ul

Fuente: https://link.springer.com/

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