Journal
ONCOTARGET
Volume 7, Issue 39, Pages 63324-63337Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11450
Keywords
sphingosine-1-phosphate; syndecan-1; TGF-beta; epithelial-mesenchymal transition; hepatocellular carcinoma
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Funding
- National Natural Science Foundation of China [11402153, 11372203]
- Talent Introduction Scientific Research Projects Funded Start-Up Funds [2082204174089]
- Excellent Young Scientist Foundation of Sichuan University of China [2015SCU04A38]
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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-beta 1 production. The limited chronic increase in TGF-beta 1 can convert HCC cells into a mesenchymal phenotype via establishing an MMP-7/Syndecan-1/TGF-beta autocrine loop. Finally, TGF-beta 1 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-beta 1 autocrine loop, and implicates targetable S1P(1)-PI3K/AKT-HPSE-MMP-7 signaling axe in HCC metastasis.
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