title: Sphingosine-1-phosphate induced epithelial-mesenchymal transition of hepatocellular carcinoma via an MMP-7/ syndecan-1/TGF-β autocrine loop.
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.
authors.affiliation: Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Xinghong
authors.initials: X
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
authors.forename: Tang
authors.initials: T
authors.lastname: Feng
authors.affiliation: Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
authors.forename: Xiaoheng
authors.initials: X
authors.lastname: Liu
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D053668:Syndecan-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D053668:Syndecan-1; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C060506:sphingosine 1-phosphate; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D013110:Sphingosine
keywords: TGF-β; epithelial-mesenchymal transition; hepatocellular carcinoma; sphingosine-1-phosphate; syndecan-1