Oncotarget

Research Papers:

Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma

Ming-Huang Chen, Chueh-Chuan Yen, Chi-Tung Cheng, Ren-Chin Wu, Shih-Chiang Huang, Chung-Shan Yu, Yi-Hsiu Chung, Chun-Yu Liu, Peter Mu-Hsin Chang, Yee Chao, Ming-Han Chen, Yu-Fen Chen, Kun-Chun Chiang, Ta-Sen Yeh, Tzu Chi Chen, Chi-Ying F. Huang and Chun-Nan Yeh _

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Oncotarget. 2015; 6:23594-23608. https://doi.org/10.18632/oncotarget.4335

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Abstract

Ming-Huang Chen1,2, Chueh-Chuan Yen2, Chi-Tung Cheng3, Ren-Chin Wu4, Shih-Chiang Huang4, Chung-Shan Yu5, Yi-Hsiu Chung6, Chun-Yu Liu1,2, Peter Mu-Hsin Chang1,2, Yee Chao1,7, Ming-Han Chen1, Yu-Fen Chen2, Kun-Chun Chiang8, Ta-Sen Yeh3, Tzu Chi Chen9, Chi-Ying F. Huang9 and Chun-Nan Yeh3

1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

2 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

3 Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan

4 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan

5 Department of Biomedical Engineering and Environmental Sciences, National Tsing-Hua University, Hsinchu, Taiwan

6 Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan

7 Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

8 Department of General Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan

9 Institute of Clinical Medicine and Institute of Biopharmaceutical Sciences National Yang-Ming University, Taipei, Taiwan

Correspondence to:

Chi-Ying F. Huang, email:

Chun-Nan Yeh, email:

Keywords: cholangiocarcinoma, sphingosine kinase 1, sphingosine-1-phosphate, SK1-I, sphingosine-1-phosphate receptor 2

Received: October 03, 2014 Accepted: May 30, 2015 Published: June 02, 2015

Abstract

Cholangiocarcinoma (CCA) is characterized by a uniquely aggressive behavior and lack of effective targeted therapies. After analyzing the gene expression profiles of seven paired intrahepatic CCA microarrays, a novel sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway and a novel target gene, SPHK1, were identified. We hypothesized that therapeutic targeting of this pathway can be used to kill intrahepatic cholangiocarcinoma (CCA) cells. High levels of SPHK1 protein expression, which was evaluated by immunohistochemical staining of samples from 96 patients with intrahepatic CCA, correlated with poor overall survival. The SPHK1 inhibitor SK1-I demonstrated potent antiproliferative activity in vitro and in vivo. SK1-I modulated the balance of ceramide-sphinogosine-S1P and induced CCA apoptosis. Furthermore, SK1-I combined with JTE013, an antagonist of the predominant S1P receptor S1PR2, inhibited the AKT and ERK signaling pathways in CCA cells. Our preclinical data suggest SPHK1/S1P pathway targeting may be an effective treatment option for patients with CCA.


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