title: 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.
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Baasanjav
authors.initials: B
authors.lastname: Uranbileg
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.|CREST, JST, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.|CREST, JST, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurano
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Enooku
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Miyagi, Japan.|CREST, JST, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saigusa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.|CREST, JST, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Ishizawa
authors.affiliation: Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kokudo
authors.affiliation: Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.|CREST, JST, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008246:Lysophospholipids / Q000378:metabolism*; D055442:Metabolome; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000446:Aldehyde-Lyases; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C022649:sphingosine 1-phosphate lyase (aldolase)