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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2
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Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2

机译：共轭胆汁酸通过激活鞘氨醇1-磷酸受体2促进胆管癌细胞侵袭性生长

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摘要

Cholangiocarcinoma (CCA) is an often fatal primary malignancy of the intra- and extrahepatic biliary tract that is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids (CBAs), which are correlated with bile duct obstruction (BDO). BDO has also recently been shown to promote CCA progression. However, whereas there is increasing evidence linking chronic cholestasis and abnormal bile acid profiles to CCA development and progression, the specific mechanisms by which bile acids may be acting to promote cholangiocarcinogenesis and invasive biliary tumor growth have not been fully established. Recent studies have shown that CBAs, but not free bile acids, stimulate CCA cell growth, and that an imbalance in the ratio of free to CBAs may play an important role in the tumorigenesis of CCA. Also, CBAs are able to activate extracellular signal-regulated kinase (ERK)1/2- and phosphatidylinositol-3-kinase/protein kinase B (AKT)-signaling pathways through sphingosine 1-phosphate receptor 2 (S1PR2) in rodent hepatocytes. In the current study, we demonstrate S1PR2 to be highly expressed in rat and human CCA cells, as well as in human CCA tissues. We further show that CBAs activate the ERK1/2- and AKT-signaling pathways and significantly stimulate CCA cell growth and invasion in vitro. Taurocholate (TCA)-mediated CCA cell proliferation, migration, and invasion were significantly inhibited by JTE-013, a chemical antagonist of S1PR2, or by lentiviral short hairpin RNA silencing of S1PR2. In a novel organotypic rat CCA coculture model, TCA was further found to significantly increase the growth of CCA cell spheroidal/"duct-like" structures, which was blocked by treatment with JTE-013. Conclusion: Our collective data support the hypothesis that CBAs promote CCA cell-invasive growth through S1PR2.
机译：胆管癌（CCA）是肝内和肝外胆道的一种常见致命原发性恶性肿瘤，通常与慢性胆汁淤积以及与胆管阻塞（BDO）相关的原发性胆汁酸和共轭胆汁酸（CBAs）水平显着升高有关。最近还显示了BDO可以促进CCA进展。但是，尽管越来越多的证据表明慢性胆汁淤积和胆汁酸异常与CCA的发生和发展有关，但胆汁酸可能通过其促进胆管癌发生和胆道浸润性肿瘤生长的具体机制尚未完全确立。最近的研究表明，CBA刺激了CCA细胞的生长，而不是游离胆汁酸，刺激了CCA细胞的生长，游离CBA的比例失衡可能在CCA的肿瘤发生中起重要作用。此外，CBA能够通过啮齿动物肝细胞中的鞘氨醇1-磷酸受体2（S1PR2）激活细胞外信号调节激酶（ERK）1 / 2-和磷脂酰肌醇-3-激酶/蛋白激酶B（AKT）信号通路。在当前的研究中，我们证明S1PR2在大鼠和人CCA细胞以及人CCA组织中高表达。我们进一步表明，CBAs激活ERK1 / 2和AKT信号通路，并在体外显着刺激CCA细胞的生长和侵袭。牛磺胆酸盐（TCA）介导的CCA细胞增殖，迁移和侵袭被S1PR2的化学拮抗剂JTE-013或S1PR2的慢病毒短发夹RNA沉默显着抑制。在新颖的器官型大鼠CCA共培养模型中，还发现TCA显着增加了CCA细胞球状/“样样”结构的生长，这种结构被JTE-013处理所阻断。结论：我们的集体数据支持以下假设：CBA通过S1PR2促进CCA细胞侵袭性生长。

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