Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Int J Mol Sci. 2018 Jun 28;19(7):1898. doi: 10.3390/ijms19071898.
Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR in epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) remain unclear. We examined the effect of several FXR ligands on EMT-related morphological changes in HCC cell lines, such as HuH-7 and Hep3B cells. FXR agonists (chenodeoxycholic acid, GW4064, and obeticholic acid)—but not an antagonist (guggulsterone)—induced actin polymerization and expression of N-cadherin and phosphorylated focal adhesion kinase, although they were less effective than transforming growth factor β (TGF-β). FXR agonist treatment enhanced TGF-β-induced EMT morphologic changes and FXR antagonist inhibited the effect of TGF-β. Thus, FXR activation enhances EMT in HCC and FXR antagonists may be EMT-suppressing drug candidates.
法尼醇 X 受体 (FXR) 是胆汁酸的受体，在肝脏胆汁酸代谢的调节中发挥重要作用。尽管已经表明 FXR 通过直接和间接机制影响肝癌的发生，但 FXR 在肝癌细胞上皮-间充质转化 (EMT)中的潜在作用尚不清楚。我们研究了几种 FXR 配体对肝癌细胞系（如 HuH-7 和 Hep3B 细胞）中 EMT 相关形态变化的影响。FXR 激动剂（鹅脱氧胆酸、GW4064 和奥贝胆酸）——而不是拮抗剂（古卡斯特酮）——诱导肌动蛋白聚合和 N-钙黏蛋白和磷酸化粘着斑激酶的表达，尽管它们的效果不如转化生长因子-β (TGF-β)。FXR 激动剂治疗增强了 TGF-β 诱导的 EMT 形态变化，而 FXR 拮抗剂抑制了 TGF-β 的作用。因此，FXR 激活增强了 HCC 中的 EMT，FXR 拮抗剂可能是 EMT 抑制药物的候选物。
