title: Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance.
abstract: 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.
  
  
  CONCLUSIONS
  The downregulation of OCT1 is associated with tumor progression and a worse patient survival.
authors.affiliation: 1st Department of Internal Medicine, Johannes Gutenberg University Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heise
authors.forename: Anja
authors.initials: A
authors.lastname: Lautem
authors.forename: Johanna
authors.initials: J
authors.lastname: Knapstein
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Schattenberg
authors.forename: Maria
authors.initials: M
authors.lastname: Hoppe-Lotichius
authors.forename: Daniel
authors.initials: D
authors.lastname: Foltys
authors.forename: Nina
authors.initials: N
authors.lastname: Weiler
authors.forename: Anca
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Arno
authors.initials: A
authors.lastname: Schad
authors.forename: Dirk
authors.initials: D
authors.lastname: Gründemann
authors.forename: Gerd
authors.initials: G
authors.lastname: Otto
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Marcus
authors.initials: M
authors.lastname: Schuchmann
authors.forename: Tim
authors.initials: T
authors.lastname: Zimmermann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D000099254:Organic Cation Transporter 3
chemical_list: D009363:Neoplasm Proteins; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D012333:RNA, Messenger; D000099254:Organic Cation Transporter 3