Abstract
A bioactive lipid, sphingosine 1-phosphate (S1P), acts extracellularly as a potent mediator, and is implicated in the progression of various cancers including hepatocellular carcinoma (HCC). S1P exerts its functions by binding to five types of specific receptors, S1P receptor 1 (S1PR1), S1PR2, S1PR3, S1PR4 and S1PR5 on the plasma membrane. However, the exact roles of S1P and each S1PR in HCC cells remain to be clarified. In the present study, we investigated the effect of S1P on the hepatocyte growth factor (HGF)-induced migration of human HCC-derived HuH7 cells, and the involvement of each S1PR. S1P dose-dependently reduced the HGF-induced migration of HuH7 cells. We found that all S1PRs exist in the HuH7 cells. Among each selective agonist for five S1PRs, CYM5520, a selective S1PR2 agonist, significantly suppressed the HGF-induced HuH7 cell migration whereas selective agonists for S1PR1, S1PR3, S1PR4 or S1PR5 failed to affect the migration. The reduction of the HGF-induced migration by S1P was markedly reversed by treatment of JTE013, a selective antagonist for S1PR2, and S1PR2- siRNA. These results strongly suggest that S1P reduces the HGF-induced HCC cell migration via S1PR2. Our findings may provide a novel potential of S1PR2 to therapeutic strategy for metastasis of HCC.
Highlights
Liver cancer is the second leading cause of cancer-related deaths [1]
We found that hepatocyte growth factor (HGF) induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and myosin phosphatase targeting subunit 1 (MYPT-1), a down-stream substrate of Rho-kinase in HuH7 cells, suggesting that p38 MAPK and Rho-kinase are activated by HGF (Fig 1)
It is recognized that HGF and its unique receptor, c-mesenchymal epithelial transition factor receptor (c-MET) are involved in activation of the “invasive program” during Hepatocellular carcinoma (HCC) metastasis, and there is a correlation between c-MET overexpression and a higher incidence of intrahepatic metastasis of HCC [14]
Summary
Liver cancer is the second leading cause of cancer-related deaths [1]. Hepatocellular carcinoma (HCC) represents about 90% of primary liver cancer cases [1]. The survival rate of HCC is poor [1,2,3]. Due to improved diagnostic methods and prolonged survival of HCC patients, recurrence, intrahepatic or extrahepatic metastases of HCC are increased in the patients of HCC [2,3]. Even liver transplantation for the patients with early-stage HCC yields a 5-year survival rate of 70%, long-term survival is not prolonged [4]. The circulating HCC cells are the main cause of recurrence and metastasis after transplantation [5,6]. The details of the metastasis of HCC has not yet been clarified
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