OATP1B3 expression is strongly associated with Wnt/β-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma

Akihisa Ueno, Yohei Masugi, Ken Yamazaki, Mina Komuta, Kathryn Effendi, Yutaka Tanami, Hanako Tsujikawa, Akihiro Tanimoto, Shigeo Okuda, Osamu Itano, Yuukou Kitagawa, Sachio Kuribayashi, Michiie Sakamoto

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22 Citations (Scopus)

Abstract

Background & Aims: 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.

Original languageEnglish
JournalJournal of Hepatology
DOIs
Publication statusAccepted/In press - 2013 Nov 8

Fingerprint

Catenins
Anions
Hepatocellular Carcinoma
Peptides
Wnt Proteins
Genes
Neoplasms
Messenger RNA
gadolinium ethoxybenzyl DTPA
Contrast Media
Reverse Transcription
Hepatocytes
Therapeutics
Immunohistochemistry
Magnetic Resonance Imaging
Sensitivity and Specificity
Cell Line
Polymerase Chain Reaction
Liver
Pharmaceutical Preparations

Keywords

  • β-Catenin
  • Gadoxetic acid
  • Hepatocellular carcinoma
  • MRI
  • OATP1B3
  • Wnt

ASJC Scopus subject areas

  • Hepatology

Cite this

@article{7b56175fe5cb4864b4954e8bb7c8497b,
title = "OATP1B3 expression is strongly associated with Wnt/β-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma",
abstract = "Background & Aims: 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.",
keywords = "β-Catenin, Gadoxetic acid, Hepatocellular carcinoma, MRI, OATP1B3, Wnt",
author = "Akihisa Ueno and Yohei Masugi and Ken Yamazaki and Mina Komuta and Kathryn Effendi and Yutaka Tanami and Hanako Tsujikawa and Akihiro Tanimoto and Shigeo Okuda and Osamu Itano and Yuukou Kitagawa and Sachio Kuribayashi and Michiie Sakamoto",
year = "2013",
month = "11",
day = "8",
doi = "10.1016/j.jhep.2014.06.008",
language = "English",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier",

}

TY - JOUR

T1 - OATP1B3 expression is strongly associated with Wnt/β-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma

AU - Ueno, Akihisa

AU - Masugi, Yohei

AU - Yamazaki, Ken

AU - Komuta, Mina

AU - Effendi, Kathryn

AU - Tanami, Yutaka

AU - Tsujikawa, Hanako

AU - Tanimoto, Akihiro

AU - Okuda, Shigeo

AU - Itano, Osamu

AU - Kitagawa, Yuukou

AU - Kuribayashi, Sachio

AU - Sakamoto, Michiie

PY - 2013/11/8

Y1 - 2013/11/8

N2 - Background & Aims: 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.

AB - Background & Aims: 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.

KW - β-Catenin

KW - Gadoxetic acid

KW - Hepatocellular carcinoma

KW - MRI

KW - OATP1B3

KW - Wnt

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U2 - 10.1016/j.jhep.2014.06.008

DO - 10.1016/j.jhep.2014.06.008

M3 - Article

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

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