Conjugated bile acids promote cholangiocarcinoma cell... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2

Liu, Runping1,2,3; Zhao, Renping1,2,3; Zhou, Xiqiao1,3; Liang, Xiuyin1; Campbell, Deanna J.W.5; Zhang, Xiaoxuan1,2; Zhang, Luyong1; Shi, Ruihua3; Wang, Guangji2; Pandak, William M.4; Sirica, Alphonse E.5,4; Hylemon, Phillip B.1,4; Zhou, Huiping1,4,6

1_Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA,_

2_Key Laboratory of New Drug Screen and Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China_

3_Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu, China_

4_McGuire Veterans Affairs Medical Center, Richmond, VA,_

5_Department of Pathology, Division of Cellular and Molecular Pathogenesis, School of Medicine, Virginia Commonwealth University, Richmond, VA,_

6_Wenzhou Medical College, Wenzhou, China_

Received 23 October 2013; Accepted 19 February 2014

Address reprint requests to: Huiping Zhou, Ph.D., Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, P.O. Box 908678, Richmond, VA 23298-0678. E-mail: [email protected]; fax: 804-828-0676.

These authors contributed equally to this work.

Drs. Zhou, Hylemon, and Sirica contributed equally to this work.

Potential conflict of interest: Nothing to report.

The work was supported by the A.D. Williams Award (to H.Z.) and the National Institutes of Health (NIH) (grant no.: R01 DK-057543; to P.B. and H.Z.). This study is also partially supported by VA Merit Award 1I01BX001390 (to H.Z.), the National Science Foundation of China (grant nos.: 81070245 and 81270489; to H.Z.), and NIH grants R01CA-83650 and 5R01CA-39225 (to A.E.S.). Funding was also provided by a NIH/National Institute of Neurological Disorders and Stroke center core grant (5P30NS047463).

See Editorial on Page 795

Abstract

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. (Hepatology 2014;60:908–918)