The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma.

Abstract

BACKGROUND/AIMS:

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: Stephan R Vavricka, Diana Jung, Michael Fried, Uwe Grützner, Peter J Meier, Gerd A Kullak-Ublick
• Journal: Journal of hepatology (J Hepatol) Vol. 40 Issue 2 Pg. 212-8 (Feb 2004) ISSN: 0168-8278 [Print] Netherlands
• PMID: 14739090 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• FOXA2 protein, human
• Liver-Specific Organic Anion Transporter 1
• Nuclear Proteins
• Organic Anion Transporters, Sodium-Independent
• SLCO1B3 protein, human
• Solute Carrier Organic Anion Transporter Family Member 1B3
• Transcription Factors
• Hepatocyte Nuclear Factor 3-beta

Topics

• Aged
• Carcinoma, Hepatocellular (genetics, physiopathology)
• DNA-Binding Proteins (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Hepatocyte Nuclear Factor 3-beta
• Humans
• Liver Neoplasms (genetics, physiopathology)
• Liver-Specific Organic Anion Transporter 1 (genetics)
• Male
• Middle Aged
• Nuclear Proteins (genetics)
• Organic Anion Transporters, Sodium-Independent (genetics)
• Promoter Regions, Genetic
• Solute Carrier Organic Anion Transporter Family Member 1B3
• Transcription Factors (genetics)
• Transcription, Genetic