Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2.
Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2.
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DOI：
10.1002/hep.27085
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发表时间：
2014-09
期刊：
影响因子：
13.5
通讯作者：
Zhou, Huiping
中科院分区：
文献类型：
--
作者：
Liu, Runping;Zhao, Renping;Zhou, Xiqiao;Liang, Xiuyin;Campbell, Deanna J. W.;Zhang, Xiaoxuan;Zhang, Luyong;Shi, Ruihua;Wang, Guangji;Pandak, William M.;Sirica, Alphonse E.;Hylemon, Phillip B.;Zhou, Huiping
胆管癌（CCA）是肝内和肝外胆道的通常致命的原发性恶性肿瘤，其通常与慢性胆汁淤积和与胆管阻塞（BDO）相关的原发性和结合胆汁酸（CBA）水平显著升高相关。BDO最近也被证明可以促进CCA进展。然而，尽管有越来越多的证据表明慢性胆汁淤积和胆汁酸异常与CCA的发展和进展有关，但胆汁酸可能促进胆管癌发生和浸润性胆管肿瘤生长的具体机制尚未完全确定。最近的研究表明，CBAs，而不是游离胆汁酸，刺激CCA细胞的生长，并在CCA的肿瘤发生中发挥重要作用，在自由CBAs的比例失衡。此外，CBAs能够通过啮齿动物肝细胞中的鞘氨醇1-磷酸受体2（S1 PR 2）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）-信号传导途径。在目前的研究中，我们证明S1 PR 2在大鼠和人CCA细胞以及人CCA组织中高度表达。我们进一步表明，CBAs激活ERK 1/2和AKT信号通路，并显着刺激CCA细胞的生长和体外侵袭。牛磺胆酸盐（TCA）介导的CCA细胞增殖，迁移和侵袭显着抑制JTE-013，S1 PR 2的化学拮抗剂，或S1 PR 2的慢病毒短发夹RNA沉默。在新的器官型大鼠CCA共培养模型中，进一步发现TCA显著增加CCA细胞球状/“导管样”结构的生长，这被JTE-013处理阻断。结论：我们的集体数据支持CBAs通过S1 PR 2促进CCA细胞侵袭性生长的假设。
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.
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影响因子：
9.7
作者：
Li, Mei-Hong;Sanchez, Teresa;Yamase, Harold;Hla, Timothy;Oo, Myat Lin;Pappalardo, Anna;Lynch, Kevin R.;Lin, Chen-Yong;Ferrer, Fernando
通讯作者：
Ferrer, Fernando
影响因子：
13.5
作者：
Studer, Elaine;Zhou, Xiqiao;Zhao, Renping;Wang, Yun;Takabe, Kazuaki;Nagahashi, Masayuki;Pandak, William M.;Dent, Paul;Spiegel, Sarah;Shi, Ruihua;Xu, Weiren;Liu, Xuyuan;Bohdan, Pat;Zhang, Luyong;Zhou, Huiping;Hylemon, Phillip B.
通讯作者：
Hylemon, Phillip B.
影响因子：
4.3
作者：
Menakongka, Apaporn;Suthiphongchai, Tuangporn
通讯作者：
Suthiphongchai, Tuangporn
影响因子：
11.2
作者：
Lepley, D;Paik, JH;Ferrer, F
通讯作者：
Ferrer, F
影响因子：
3.6
作者：
Dumur, Catherine I.;Campbell, Deanna J. W.;Sirica, Alphonse E.
通讯作者：
Sirica, Alphonse E.