Akihisa Ueno1, Yohei Masugi2, Ken Yamazaki2, Mina Komuta3, Kathryn Effendi2, Yutaka Tanami4, Hanako Tsujikawa2, Akihiro Tanimoto4, Shigeo Okuda4, Osamu Itano5, Yuko Kitagawa5, Sachio Kuribayashi4, Michiie Sakamoto6. 1. Department of Pathology, School of Medicine, Keio University, Tokyo, Japan; Department of Diagnostic Radiology, School of Medicine, Keio University, Tokyo, Japan. 2. Department of Pathology, School of Medicine, Keio University, Tokyo, Japan. 3. Department of Pathology, School of Medicine, Keio University, Tokyo, Japan; Department of Translational Cell & Tissue Research, University Hospitals Leuven, Leuven, Belgium. 4. Department of Diagnostic Radiology, School of Medicine, Keio University, Tokyo, Japan. 5. Department of Surgery, School of Medicine, Keio University, Tokyo, Japan. 6. Department of Pathology, School of Medicine, Keio University, Tokyo, Japan. Electronic address: msakamot@z5.keio.jp.
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.
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.
Authors: Ryan L Brunsing; Dennis H Chen; Alexandra Schlein; Tanya Wolfson; Anthony Gamst; Adrija Mamidipalli; Naik Vietti Violi; Robert M Marks; Bachir Taouli; Rohit Loomba; Yuko Kono; Claude B Sirlin Journal: Radiol Imaging Cancer Date: 2019-11-29