title: The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma.
abstract: OBJECTIVE
  The organic anion transporting polypeptides (OATPs) mediate the uptake of numerous amphipathic compounds into hepatocytes. Our aim was to study the expression and regulation of OATP8 (OATP1B3, SLC21A8/SLCO1B3) and OATP-C (OATP1B1, SLC21A6/SLCO1B1) in hepatocellular carcinomas (HCC).
  
  
  METHODS
  RNA and protein levels in 13 paired HCC and adjacent non-tumor liver samples were quantified by real-time polymerase chain reaction or Western blot, respectively. The OATP8 and OATP-C gene promoters were characterized by luciferase reporter assays and electrophoretic mobility shift assays (EMSA).
  
  
  RESULTS
  The expression of OATP8 was decreased in 60% of HCC compared to surrounding non-tumor liver tissue, on both the mRNA and protein levels. Expression of the liver-enriched transcription factor hepatocyte nuclear factor 3beta (HNF3beta) was increased in 70% of HCC and correlated inversely with OATP8 mRNA (r=-0.75, P<0.05) and protein. In contrast to OATP8, expression of OATP-C was not significantly decreased in HCC. In transfected Huh7 cells, OATP8 promoter activity was inhibited by 70% when HNF3beta was cotransfected. An HNF3beta binding site was located at nt -39/-23 by EMSA. The OATP-C promoter was not inhibited by HNF3beta.
  
  
  CONCLUSIONS
  HNF3beta represses transcription of the OATP8 but not the OATP-C gene, providing a mechanism for reduced expression of OATP8 in HCC.
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, Division of Gastroenterology and Hepatology, University Hospital, CH-8091 Zurich, Switzerland.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Vavricka
authors.forename: Diana
authors.initials: D
authors.lastname: Jung
authors.forename: Michael
authors.initials: M
authors.lastname: Fried
authors.forename: Uwe
authors.initials: U
authors.lastname: Grützner
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meier
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000503:physiopathology*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D011401:Promoter Regions, Genetic; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; D027381:Liver-Specific Organic Anion Transporter 1; D009687:Nuclear Proteins; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta