title: OATP1B3 expression is strongly associated with Wnt/β-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma.
abstract: OBJECTIVE
  In the current era of emerging molecular targeted drugs, it is necessary to identify before treatment the specific subclass to which a tumour belongs. Gadoxetic acid is a liver-specific contrast agent that is preferentially taken up by hepatocytes. Therefore, gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) should provide precise molecular information about hepatocellular carcinomas (HCCs). The aim of this study was to investigate the transporters of gadoxetic acid in HCC comprehensively and to analyse the molecular regulatory mechanism of such transporters.
  
  
  METHODS
  Expression levels of transporters, transcriptional factors and Wnt target genes in clinical samples were examined by quantitative real-time reverse transcription polymerase chain reaction and immunohistochemistry. LiCl treatment of the HCC cell line KYN-2 was conducted in vitro to assess the effects of Wnt signalling activity.
  
  
  RESULTS
  Comprehensive analyses of transporter mRNAs and protein expressions revealed that the organic anion transporting polypeptide 1B3 (OATP1B3) had the strongest correlation with tumour enhancement in hepatobiliary-phase images of EOB-MRI. Association analysis with OATP1B3 expression revealed significant correlation with the expression of Wnt/β-catenin target genes. Further, LiCl treatment induced OATP1B3 mRNA expression in KYN-2 cells, indicating a strong association between OATP1B3 expression and Wnt/β-catenin signalling. The sensitivity and specificity to predict Wnt/β-catenin-activated HCC using tumour enhancement in EOB-MRI were 78.9% and 81.7%, respectively.
  
  
  CONCLUSIONS
  OATP1B3 was confirmed as the most important transporter mediating HCC enhancement in EOB-MRI. OATP1B3 expression showed a strong association with the expression of Wnt/β-catenin target genes, therefore, OATP1B3-upregulated HCC likely represents a specific subclass of Wnt/β-catenin-activated HCC.
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan; Department of Diagnostic Radiology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Ueno
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Masugi
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan; Department of Translational Cell & Tissue Research, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Mina
authors.initials: M
authors.lastname: Komuta
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Effendi
authors.affiliation: Department of Diagnostic Radiology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tanami
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Hanako
authors.initials: H
authors.lastname: Tsujikawa
authors.affiliation: Department of Diagnostic Radiology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tanimoto
authors.affiliation: Department of Diagnostic Radiology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Itano
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Department of Diagnostic Radiology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Kuribayashi
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan. Electronic address: msakamot@z5.keio.jp.
authors.forename: Michiie
authors.initials: M
authors.lastname: Sakamoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000378:metabolism; D005260:Female; D019786:Gadolinium DTPA / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D003287:Contrast Media; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D051176:beta Catenin; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA
keywords: Gadoxetic acid; Hepatocellular carcinoma; MRI; OATP1B3; Wnt; β-Catenin