Oncotarget

Research Papers:

Sphingosine-1-phosphate induced epithelial-mesenchymal transition of hepatocellular carcinoma via an MMP-7/ syndecan-1/TGF-β autocrine loop

Ye Zeng, Xinghong Yao, Li Chen, Zhiping Yan, Jingxia Liu, Yingying Zhang, Tang Feng, Jiang Wu and Xiaoheng Liu _

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Oncotarget. 2016; 7:63324-63337. https://doi.org/10.18632/oncotarget.11450

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Abstract

Ye Zeng1, Xinghong Yao2, Li Chen2, Zhiping Yan1, Jingxia Liu1, Yingying Zhang1, Tang Feng1, Jiang Wu1, Xiaoheng Liu1

1Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China

2State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China

Correspondence to:

Ye Zeng, email: [email protected]

Xiaoheng Liu, email: [email protected]

Keywords: sphingosine-1-phosphate, syndecan-1, TGF-β, epithelial-mesenchymal transition, hepatocellular carcinoma

Received: June 14, 2016     Accepted: August 15, 2016     Published: August 20, 2016

ABSTRACT

Sphingosine-1-phosphate (S1P) induces epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). However, its underlying mechanism remains largely unknown. In the present study, we investigated the correlation between S1P and syndecan-1 in HCC, the molecular mechanism involved, as well as their roles in EMT of HCC. Results revealed a high serum S1P level presents in patients with HCC, which positively correlated with the serum syndecan-1 level. A significant inverse correlation existed between S1P1 and syndecan-1 in HCC tissues. S1P elicits activation of the PI3K/AKT signaling pathways via S1P1, which triggers HPSE, leading to increases in expression and activity of MMP-7 and leading to shedding and suppression of syndecan-1. The loss of syndecan-1 causes an increase in TGF-β1 production. The limited chronic increase in TGF-β1 can convert HCC cells into a mesenchymal phenotype via establishing an MMP-7/Syndecan-1/TGF-β autocrine loop. Finally, TGF-β1 and syndecan-1 are essential for S1P-induced epithelial to mesenchymal transition. Taken together, our study demonstrates that S1P induces advanced tumor phenotypes of HCC via establishing an MMP-7/syndecan-1/TGF-β1 autocrine loop, and implicates targetable S1P1-PI3K/AKT-HPSE-MMP-7 signaling axe in HCC metastasis.


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