Abstract
Although sphingosine 1-phosphate (S1P) has been reported to play an important role in cancer pathophysiology, little is known about S1P and hepatocellular carcinoma (HCC). To clarify the relationship between S1P and HCC, 77 patients with HCC who underwent surgical treatment were consecutively enrolled in this study. In addition, S1P and its metabolites were quantitated by LC-MS/MS. The mRNA levels of sphingosine kinases (SKs), which phosphorylate sphingosine to generate S1P, were increased in HCC tissues compared with adjacent non-HCC tissues. Higher mRNA levels of SKs in HCC were associated with poorer differentiation and microvascular invasion, whereas a higher level of SK2 mRNA was a risk factor for intra- and extra-hepatic recurrence. S1P levels, however, were unexpectedly reduced in HCC compared with non-HCC tissues, and increased mRNA levels of S1P lyase (SPL), which degrades S1P, were observed in HCC compared with non-HCC tissues. Higher SPL mRNA levels in HCC were associated with poorer differentiation. Finally, in HCC cell lines, inhibition of the expression of SKs or SPL by siRNA led to reduced proliferation, invasion and migration, whereas overexpression of SKs or SPL enhanced proliferation. In conclusion, increased SK and SPL mRNA expression along with reduced S1P levels were more commonly observed in HCC tissues compared with adjacent non-HCC tissues and were associated with poor differentiation and early recurrence. SPL as well as SKs may be therapeutic targets for HCC treatment.
Highlights
Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator that functions in a wide variety of cellular responses
MRNA expressions of S1P receptors in hepatocellular carcinoma (HCC) tissues were examined, showing the increase in S1P1 and S1P2 mRNA levels (S1 Fig). These results suggest that the enhanced mRNA levels of S1P lyase (SPL) may explain the reduced levels of S1P in HCC tissues compared with non-tumorous tissues, despite the higher levels of sphingosine kinases (SKs) mRNAs
To gain insight regarding the significance of the high mRNA levels of SKs or SPL in HCC, we examined the potential effect of inhibiting the expression of SKs or SPL in HCC cell lines
Summary
Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator that functions in a wide variety of cellular responses. S1P was first shown to play a role as an intracellular messenger in the mitogenic activity of PDGF or serum in cultured fibroblasts [1]. Some of the diverse effects of S1P, such as stimulation of cell proliferation or contractility, have been shown to be sensitive to pertussis toxin [3] or ADP-ribosyltransferase C3 from Clostridium botulinum [4]. These findings indicate that S1P, as an extracellular mediator, activates a receptor coupled to G protein(s). Substantial evidence for the phenotypes of S1P receptor mutants [6,7,8,9] suggests that S1P has normal roles in vivo as well as potentially pathophysiological roles as a circulating paracrine mediator that is stored and released from platelets [10] or erythrocytes [11]
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