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

• Published in: Oncotarget 2016-09, Vol.7 (39), p.63324-63337
• Main Authors: Zeng, Ye, Yao, Xinghong, Chen, Li, Yan, Zhiping, Liu, Jingxia, Zhang, Yingying, Feng, Tang, Wu, Jiang, Liu, Xiaoheng
• Format: Article
• Language: English
• Subjects: Aged; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Enzyme Inhibitors - pharmacology; Epithelial-Mesenchymal Transition - drug effects; Female; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lysophospholipids - metabolism; Male; Matrix Metalloproteinase 7 - metabolism; Middle Aged; Phenotype; Research Paper; Signal Transduction; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Syndecan-1 - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.11450

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.