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 3β (HNF3β) 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 HNF3β was cotransfected. An HNF3β binding
site was located at nt −39/−23 by EMSA. The OATP-C promoter was not inhibited by HNF3β.
Conclusions: HNF3β represses transcription of the OATP8 but not the OATP-C gene, providing a mechanism for reduced expression of OATP8 in HCC.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The superfamily of organic anion transporting polypeptides.Biochim Biophys Acta. 2003; 1609: 1-18
- Hepatic transport of bile salts.Semin Liver Dis. 2000; 20: 273-292
- Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1.J Biol Chem. 1999; 274: 17159-17163
- A novel human hepatic organic anion transporting polypeptide (OATP2).J Biol Chem. 1999; 274: 37161-37168
- A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane.Am J Physiol. 2000; 278: G156-G164
- Organic anion transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver.Gastroenterology. 2001; 120: 525-533
- Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6.J Biol Chem. 2001; 276: 9626-9630
- Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide.J Biol Chem. 2000; 275: 23161-23168
- Hepatic uptake of cholecystokinin octapeptide by organic anion transporting polypeptides Oatp4 and OATP8 of rat and human liver.Gastroenterology. 2001; 121: 1185-1190
- Lst-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers.Gastroenterology. 2001; 120: 1689-1699
- Characterization of the human OATP-C (SLC21A6) gene promoter and regulation of liver-specific OATP genes by hepatocyte nuclear factor 1α.J Biol Chem. 2001; 276: 37206-37214
- Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression.Hepatology. 2003; 37: 622-631
- Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor.Gastroenterology. 2002; 122: 1954-1966
- Multiple factors regulate the rat liver basolateral sodium-dependent bile acid cotransporter gene promoter.J Biol Chem. 1996; 271: 15211-15221
- Elevated levels of hepatocyte nuclear factor 3beta in mouse hepatocytes influence expression of genes involved in bile acid and glucose homeostasis.Mol Cell Biol. 2000; 20: 8264-8282
- Adenovirus-mediated increase in HNF-3beta or HNF-3alpha shows differences in levels of liver glycogen and gene expression.Hepatology. 2002; 35: 30-39
- Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma.Cancer Res. 2001; 61: 3176-3181
- The hepatocyte nuclear factor 3 (HNF3 or FOXA) family in metabolism.Trends Endocrinol Metab. 2000; 11: 281-285
- Hepatocyte nuclear factor 3β contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein.Mol Cell Biol. 1992; 12: 3723-3732
- Liver-enriched transcription factors in liver function and development. Part I: the hepatocyte nuclear factor network and liver-specific gene expression.Pharmacol Rev. 2002; 54: 129-158
- Overproduction of a truncated hepatocyte nuclear factor 3 protein inhibits expression of liver-specific genes in hepatoma cells.Mol Cell Biol. 1995; 15: 5453-5460
- Detection of the human organic anion transporters SLC21A6 (OATP2) and SLC21A8 (OATP8) in liver and hepatocellular carcinoma.Lab Invest. 2003; 83: 527-538
- Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei.Nucleic Acids Res. 1983; 11: 1475-1489
- Molecular genetics of early liver development.Annu Rev Physiol. 1996; 58: 231-251
- Hepatocyte nuclear factor 3beta (Foxa2) is dispensable for maintaining the differentiated state of the adult hepatocyte.Mol Cell Biol. 2000; 20: 5175-5183
- HNF-3 beta is essential for node and notochord formation in mouse development.Cell. 1994; 78: 561-574
- The transcription factor HNF3beta is required in visceral endoderm for normal primitive streak morphogenesis.Development. 1998; 125: 3015-3025
- Regulation of a transcription factor network required for differentiation and metabolism.Science. 1998; 281: 692-695
- A role for HNF-3 in the regulation of the HNF-1 gene of the Atlantic salmon.Mol Genet Genomics. 2002; 266: 832-837
- Glucagon gene expression is negatively regulated by hepatocyte nuclear factor 3 beta.Mol Cell Biol. 1994; 14: 3514-3523
- Activity of the rat liver-specific aldolase B promoter is restrained by HNF3.Nucleic Acids Res. 1994; 22: 1242-1246
- Characterization of hepatic-specific regulatory elements in the promoter region of the human cholesterol 7α-hydroxylase gene.J Biol Chem. 1997; 272: 3444-3452
- Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas.Gastroenterology. 1997; 113: 1295-1305
- Pharmacogenomics of organic anion-transporting polypeptides (OATP).Adv Drug Deliv Rev. 2002; 54: 1343-1352
- Hepatic uptake of the magnetic resonance imaging contrast agent gadoxetate by the organic anion transporting polypeptide Oatp1.J Pharmacol Exp Ther. 1999; 290: 153-157
- Molecular mechanisms for the hepatic uptake of magnetic resonance imaging contrast agents.Biochem Biophys Res Commun. 1999; 257: 746-752
- Further evidence of the usefulness of bile acids as molecules for shuttling cytostatic drugs toward liver tumors.J Hepatol. 1999; 31: 521-528
- Low in vivo toxicity of a novel cisplatin-ursodeoxycholic derivative (Bamet-UD2) with enhanced cytostatic activity versus liver tumors.J Pharmacol Exp Ther. 2001; 297: 1106-1112
- Liver organotropism and biotransformation of a novel platinum-ursodeoxycholate derivative, Bamet-UD2, with enhanced antitumour activity.J Drug Target. 2001; 9: 185-200
- Carriers involved in targeting the cytostatic bile acid-cisplatin derivatives cis-diammine-chloro-cholylglycinate-platinum (II) and cis-diammine-bisursodeoxycholate-platinum (II) toward liver cells.Mol Pharmacol. 2002; 61: 853-860
Article info
Publication history
Accepted:
October 1,
2003
Received in revised form:
September 27,
2003
Received:
May 9,
2003
Identification
Copyright
© 2003 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
