OATP1B3 表达与 Wnt/β-连环蛋白信号通路密切相关，是肝癌中钆塞酸的转运体。
OATP1B3 expression is strongly associated with Wnt/β-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma.
机构信息
Department of Pathology, School of Medicine, Keio University, Tokyo, Japan; Department of Diagnostic Radiology, School of Medicine, Keio University, Tokyo, Japan.
Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
出版信息
J Hepatol. 2014 Nov;61(5):1080-7. doi: 10.1016/j.jhep.2014.06.008. Epub 2014 Jun 16.
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.
背景与目的
在当前新兴分子靶向药物时代，有必要在治疗前确定肿瘤所属的特定亚类。钆塞酸是一种肝脏特异性对比剂，优先被肝细胞摄取。因此，钆塞酸增强磁共振成像（EOB-MRI）应该为肝细胞癌（HCC）提供关于肝癌的精确分子信息。本研究旨在全面研究 HCC 中 gadoxetic acid 的转运蛋白，并分析这些转运蛋白的分子调控机制。
方法
通过定量实时逆转录聚合酶链反应和免疫组织化学检测临床样本中转运蛋白、转录因子和 Wnt 靶基因的表达水平。在体外用 LiCl 处理 HCC 细胞系 KYN-2 以评估 Wnt 信号活性的影响。
结果
全面分析转运体 mRNAs 和蛋白表达显示，有机阴离子转运多肽 1B3（OATP1B3）与 EOB-MRI 肝胆期图像中肿瘤增强的相关性最强。与 OATP1B3 表达的关联分析显示与 Wnt/β-catenin 靶基因的表达有显著相关性。此外，LiCl 处理诱导 KYN-2 细胞中 OATP1B3 mRNA 的表达，表明 OATP1B3 表达与 Wnt/β-catenin 信号之间存在很强的关联。使用 EOB-MRI 中肿瘤增强来预测 Wnt/β-catenin 激活 HCC 的灵敏度和特异性分别为 78.9%和 81.7%。
结论
OATP1B3 被确认为介导 EOB-MRI 中 HCC 增强的最重要转运体。OATP1B3 表达与 Wnt/β-catenin 靶基因的表达呈强相关性，因此，OATP1B3 上调的 HCC 可能代表 Wnt/β-catenin 激活 HCC 的特定亚类。
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