Increased mRNA Levels of Sphingosine Kinases and S1P Lyase and Reduced Levels of S1P Were Observed in Hepatocellular Carcinoma in Association with Poorer Differentiation and Earlier Recurrence

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.

Possible involvement of PS-PLA1 and lysophosphatidylserine receptor (LPS1) in hepatocellular carcinoma

“…Quantitative real-time PCR of LPSRs and PS-PLA1. Quantitative real-time PCR was performed as previously described 6 . Human LPS1, LPS2, LPS3, PS-PLA1 and eukaryotic ribosomal 18 S primers and probes (TaqMan Gene Expression Assays) were obtained from Applied Biosystems (Hs00271105_s1, Hs00274326_s1, Hs00261404_s1, Hs01056915_m1 and Hs99999901_s1).…”

Sphingosine-1 Phosphate: A New Modulator of Immune Plasticity in the Tumor Microenvironment

“…Even an overwhelming amount of data indicate that increased S1P levels were associated with cancer progression, many recent reports showed disconcerting results: (i) in patients with hepatocellular carcinoma, a decrease in S1P levels in HCC tissue was linked to less tumor differentiation and more microvascular invasion ( 57 ); (ii) specific inhibition of SphK1 in 1483 head and neck carcinoma cells with PF-543 did not affect cell proliferation or survival ( 84 ), and (iii) pharmacological and molecular inhibition of SphK1 and SphK2 did not affect tumor cell growth, both in vitro and in vivo ( 85 ). The discrepancies of these results with many opposing evidences warrant further investigation.…”

Identification of novel biomarkers of hepatocellular carcinoma by high‐definition mass spectrometry: Ultrahigh‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry and desorption electrospray ionization mass spectrometry imaging

“…Human liver was obtained from HCC patients at the Hepatobiliary Pancreatic Surgery Division, Department of Surgery, at the University of Tokyo Hospital between January 2013 and October 2014. Patient information was described in a previous report . The research ethics committee of the Faculty of Medicine, University of Tokyo approved the present study, which was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.…”

“…Patient information was described in a previous report. 4 The research ethics committee of the Faculty of Medicine, University of Tokyo approved the present study, which was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. All patients provided written informed consent for the use of clinical samples.…”