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

// Ye Zeng 1 , Xinghong Yao 2 , Li Chen 2 , Zhiping Yan 1 , Jingxia Liu 1 , Yingying Zhang 1 , Tang Feng 1 , Jiang Wu 1 , Xiaoheng Liu 1 1 Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China 2 State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China Correspondence to: Ye Zeng, email: yeQgzeng@gmail.com Xiaoheng Liu, email: liuxiaohg@scu.edu.cn 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 S1P 1 and syndecan-1 in HCC tissues. S1P elicits activation of the PI3K/AKT signaling pathways via S1P 1 , 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 S1P 1 -PI3K/AKT-HPSE-MMP-7 signaling axe in HCC metastasis.