Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance

BMC Cancer

Michael Heise²  Anja Lautem²  Johanna Knapstein⁴  Jörn M Schattenberg⁴  Maria Hoppe-Lotichius²  Daniel Foltys²  Nina Weiler²  Anca Zimmermann⁴  Arno Schad¹  Dirk Gründemann³  Gerd Otto²  Peter R Galle⁴  Marcus Schuchmann⁴  Tim Zimmermann⁴ 

[1] Institute of Pathology, Johannes Gutenberg University Mainz, Germany

[2] Department of Hepatobiliary and Transplantation Surgery, Johannes Gutenberg University Mainz, Germany

[3] Department of Pharmacology, University of Cologne, Germany

[4] 1st Department of Internal Medicine, Johannes Gutenberg University Mainz, Germany

关键词: HCC;    Hepatocellular carcinoma;    SLC22A3;    SLC22A1;    OCT3;    OCT1;   

Others  :  1080498
DOI  :  10.1186/1471-2407-12-109

 received in 2011-08-08, accepted in 2012-03-22,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Heise et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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