人类有机阴离子转运多肽8（SLCO1B3）基因在肝细胞癌中受到肝细胞核因子3β的转录抑制。

The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma.

作者信息

Vavricka Stephan R, Jung Diana, Fried Michael, Grützner Uwe, Meier Peter J, Kullak-Ublick Gerd A

机构信息

Laboratory of Molecular Gastroenterology and Hepatology, Division of Gastroenterology and Hepatology, University Hospital, CH-8091 Zurich, Switzerland.

出版信息

J Hepatol. 2004 Feb;40(2):212-8. doi: 10.1016/j.jhep.2003.10.008.

DOI:10.1016/j.jhep.2003.10.008

PMID:14739090

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 3beta (HNF3beta) 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 HNF3beta was cotransfected. An HNF3beta binding site was located at nt -39/-23 by EMSA. The OATP-C promoter was not inhibited by HNF3beta.

CONCLUSIONS

HNF3beta represses transcription of the OATP8 but not the OATP-C gene, providing a mechanism for reduced expression of OATP8 in HCC.

摘要

背景/目的：有机阴离子转运多肽（OATPs）介导多种两亲性化合物摄取进入肝细胞。我们的目的是研究OATP8（OATP1B3，SLC21A8/SLCO1B3）和OATP-C（OATP1B1，SLC21A6/SLCO1B1）在肝细胞癌（HCC）中的表达及调控。

方法

分别通过实时聚合酶链反应或蛋白质印迹法对13对HCC及其相邻非肿瘤肝组织样本中的RNA和蛋白质水平进行定量分析。通过荧光素酶报告基因检测和电泳迁移率变动分析（EMSA）对OATP8和OATP-C基因启动子进行表征。

结果

与周围非肿瘤肝组织相比，60%的HCC中OATP8在mRNA和蛋白质水平上表达均降低。70%的HCC中肝富集转录因子肝细胞核因子3β（HNF3β）表达增加，且与OATP8 mRNA（r = -0.75，P < 0.05）和蛋白质呈负相关。与OATP8相反，HCC中OATP-C的表达未显著降低。在转染的Huh7细胞中，共转染HNF3β时，OATP8启动子活性被抑制70%。通过EMSA确定HNF3β结合位点位于nt -39/-23处。OATP-C启动子未被HNF3β抑制。