Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma

Lautem,Anja; Heise,Michael; Gräsel,Andreas; Hoppe‑Lotichius,Maria; Weiler,Nina; Foltys,Daniel; Knapstein,Johanna; Schattenberg,Jörn   M.; Schad,Arno; Zimmermann,Anca; Otto,Gerd; Lang,Hauke; Galle,Peter  R.; Schuchmann,Marcus; Zimmermann,Tim

doi:10.3892/ijo.2013.1840

Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma

Authors:
- 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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Affiliations: Department of Hepatobiliary and Transplantation Surgery, Johannes Gutenberg University Mainz, Mainz, Germany, First Department of Internal Medicine, Johannes Gutenberg University Mainz, Mainz, Germany, Institute of Pathology, Johannes Gutenberg University Mainz, Mainz, Germany, Department of General and Abdominal Surgery, Johannes Gutenberg University Mainz, Mainz, Germany
Published online on: February 22, 2013 https://doi.org/10.3892/ijo.2013.1840
Pages: 1297-1304

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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.

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1	Khan SA, Toledano MB and Taylor-Robinson SD: Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford). 10:77–82. 2008. View Article : Google Scholar : PubMed/NCBI
2	Seol MA, Chu IS, Lee MJ, Yu GR, Cui XD, Cho BH, Ahn EK, Leem SH, Kim IH and Kim DG: Genome-wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma. BMC Cancer. 11:782011. View Article : Google Scholar : PubMed/NCBI
3	Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D, Kaczirek K, Roka R, Freimann-Pircher S and Gruenberger T: Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol. 11:1142–1148. 2010. View Article : Google Scholar : PubMed/NCBI
4	Xu L, Hausmann M, Dietmaier W, Kellermeier S, Pesch T, Stieber-Gunckel M, Lippert E, Klebl F and Rogler G: Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines. BMC Cancer. 10:3022010. View Article : Google Scholar : PubMed/NCBI
5	White DL, Radich J, Soverini S, Saunders VA, Frede AK, Dang P, Cilloni D, Lin P, Mongay L, Woodman R, Manley P, Slader C, Kim DW, Pane F, Martinelli G, Saglio G and Hughes TP: Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinib. Haematologica. 97:907–914. 2012. View Article : Google Scholar
6	Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A, Chen Y, Komori T, Gray JW, Chen X, Lippard SJ and Giacomini KM: Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 66:8847–8857. 2006. View Article : Google Scholar : PubMed/NCBI
7	Jonker JW, Wagenaar E, Van Eijl S and Schinkel AH: Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol. 23:7902–7908. 2003.PubMed/NCBI
8	Zwart R, Verhaagh S, Buitelaar M, Popp-Snijders C and Barlow DP: Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol. 21:4188–4196. 2001. View Article : Google Scholar : PubMed/NCBI
9	Heise M, Lautem A, Knapstein J, Schattenberg JM, Hoppe-Lotichius M, Foltys D, Weiler N, Zimmermann A, Schad A, Gründemann D, Otto G, Galle PR, Schuchmann M and Zimmermann T: Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance. BMC Cancer. 12:1092012. View Article : Google Scholar : PubMed/NCBI
10	Chang Q, Chen J, Beezhold KJ, Castranova V, Shi X and Chen F: JNK1 activation predicts the prognostic outcome of the human hepatocellular carcinoma. Mol Cancer. 8:642009. View Article : Google Scholar : PubMed/NCBI
11	Okabe H, Satoh S, Kato T, Kitahara O, Yanagawa R, Yamaoka Y, Tsunoda T, Furukawa Y and Nakamura Y: Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res. 61:2129–2137. 2001.
12	Park T, Yi SG, Shin YK and Lee S: Combining multiple microarrays in the presence of controlling variables. Bioinformatics. 22:1682–1689. 2006. View Article : Google Scholar : PubMed/NCBI
13	Verhaagh S, Schweifer N, Barlow DP and Zwart R: Cloning of the mouse and human solute carrier 22a3 (Slc22a3/SLC22A3) identifies a conserved cluster of three organic cation transporters on mouse chromosome 17 and human 6q26-q27. Genomics. 55:209–218. 1999. View Article : Google Scholar
14	Zwart R, Sleutels F, Wutz A, Schinkel AH and Barlow DP: Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes. Genes Dev. 15:2361–2366. 2001. View Article : Google Scholar : PubMed/NCBI
15	Schaeffeler E, Hellerbrand C, Nies AT, Winter S, Kruck S, Hofmann U, van der Kuip H, Zanger UM, Koepsell H and Schwab M: DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma. Genome Med. 3:822011. View Article : Google Scholar : PubMed/NCBI
16	Kitada N, Takara K, Minegaki T, Itoh C, Tsujimoto M, Sakaeda T and Yokoyama T: Factors affecting sensitivity to antitumor platinum derivatives of human colorectal tumor cell lines. Cancer Chemother Pharmacol. 62:577–584. 2008. View Article : Google Scholar : PubMed/NCBI
17	Yokoo S, Masuda S, Yonezawa A, Terada T, Katsura T and Inui K: Significance of organic cation transporter 3 (SLC22A3) expression for the cytotoxic effect of oxaliplatin in colorectal cancer. Drug Metab Dispos. 36:2299–2306. 2008. View Article : Google Scholar : PubMed/NCBI
18	Eckel F and Schmid RM: Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer. 96:896–902. 2007. View Article : Google Scholar : PubMed/NCBI
19	Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M and Bridgewater J: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 362:1273–1281. 2010. View Article : Google Scholar : PubMed/NCBI
20	Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E, Keil A, Eichelbaum M and Koepsell H: Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. 12:591–595. 2002. View Article : Google Scholar : PubMed/NCBI
21	Sakata T, Anzai N, Shin HJ, Noshiro R, Hirata T, Yokoyama H, Kanai Y and Endou H: Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochem Biophys Res Commun. 313:789–793. 2004. View Article : Google Scholar
22	Chen L, Pawlikowski B, Schlessinger A, More SS, Stryke D, Johns SJ, Portman MA, Chen E, Ferrin TE, Sali A and Giacomini KM: Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet Genomics. 20:687–699. 2010. View Article : Google Scholar : PubMed/NCBI
23	Lazar A, Gründemann D, Berkels R, Taubert D, Zimmermann T and Schömig E: Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet. 48:226–230. 2003. View Article : Google Scholar : PubMed/NCBI
24	Sakata T, Anzai N, Kimura T, Miura D, Fukutomi T, Takeda M, Sakurai H and Endou H: Functional analysis of human organic cation transporter OCT3 (SLC22A3) polymorphisms. J Pharmacol Sci. 113:263–266. 2010. View Article : Google Scholar : PubMed/NCBI
25	Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM and Giacomini KM: Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 117:1422–1431. 2007. View Article : Google Scholar : PubMed/NCBI
26	Song IS, Shin HJ and Shin JG: Genetic variants of organic cation transporter 2 (OCT2) significantly reduce metformin uptake in oocytes. Xenobiotica. 38:1252–1262. 2008. View Article : Google Scholar : PubMed/NCBI
27	Cui R, Okada Y, Jang SG, Ku JL, Park JG, Kamatani Y, Hosono N, Tsunoda T, Kumar V, Tanikawa C, Kamatani N, Yamada R, Kubo M, Nakamura Y and Matsuda K: Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population. Gut. 60:799–805. 2011. View Article : Google Scholar : PubMed/NCBI
28	Eeles RA, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth SK, Mulholland S, Leongamornlert DA, Edwards SM, Morrison J, Field HI, Southey MC, Severi G, Donovan JL, Hamdy FC, Dearnaley DP, Muir KR, Smith C, Bagnato M, Ardern-Jones AT, Hall AL, O’Brien LT, Gehr-Swain BN, Wilkinson RA, Cox A, Lewis S, Brown PM, Jhavar SG, Tymrakiewicz M, Lophatananon A, Bryant SL; UK Genetic Prostate Cancer Study Collaborators; British Association of Urological Surgeons' Section of Oncology; UK ProtecT Study Collaborators; Horwich A, Huddart RA, Khoo VS, Parker CC, Woodhouse CJ, Thompson A, Christmas T, Ogden C, Fisher C, Jamieson C, Cooper CS, English DR, Hopper JL, Neal DE and Easton DF: Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet. 40:316–321. 2008. View Article : Google Scholar : PubMed/NCBI