title: Serum sphingolipidomic analyses reveal an upregulation of C16-ceramide and sphingosine-1-phosphate in hepatocellular carcinoma.
abstract: We have recently shown that major alterations of serum sphingolipid metabolites in chronic liver disease associate significantly with the stage of liver fibrosis in corresponding patients. In the current study we assessed via mass spectrometry serum concentrations of sphingolipid metabolites in a series of 122 patients with hepatocellular carcinoma (HCC) compared to an age- and sex-matched series of 127 patients with cirrhosis. We observed a highly significant upregulation of long and very long chain ceramides (C16-C24) in the serum of patients with HCC as compared to patients with cirrhosis (P < 0.001). Accordingly, dihydro-ceramides, synthetic precursors of ceramides and notably sphingosine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) were upregulated in patients with HCC (P < 0.001). Especially the diagnostic accuracy of C16-ceramide and S1P, assessed by receiver operating curve (ROC) analysis, showed a higher area under the curve (AUC) value as compared to alpha fetoprotein (AFP) (0.999 and 0.985 versus 0.823, P < 0.001 respectively). In conclusion, serum levels of sphingolipid metabolites show a significant upregulation in patients with HCC as compared to patients with cirrhosis. Particularly C16-ceramide and S1P may serve as novel diagnostic markers for the identification of HCC in patients with liver diseases. Our data justify further investigations on the role of sphingolipids in HCC.
authors.affiliation: Goethe University Hospital, Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany.|Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Grammatikos
authors.affiliation: Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Schoell
authors.affiliation: Pharmazentrum Frankfurt, Institut für klinische Pharmakologie, Goethe University Hospital, Frankfurt am Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Goethe University, Department of Medicine, Institute of Biostatistics and Mathematical Modelling, Frankfurt am Main, Germany.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bon
authors.affiliation: Goethe University, Department of Medicine, Institute of Biostatistics and Mathematical Modelling, Frankfurt am Main, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Farnik
authors.affiliation: Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Köberle
authors.affiliation: Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Piiper
authors.affiliation: Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kronenberger
authors.affiliation: Goethe University Hospital, Medizinische Klinik 1, Frankfurt am Main, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Waidmann
authors.affiliation: Goethe University Hospital, Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000175:diagnosis / Q000473:pathology*; D002518:Ceramides / Q000096:biosynthesis / Q000097:blood*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000473:pathology*; D008113:Liver Neoplasms / Q000097:blood / Q000175:diagnosis / Q000473:pathology*; D008246:Lysophospholipids / Q000096:biosynthesis / Q000097:blood*; D008297:Male; D008875:Middle Aged; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D002518:Ceramides; D008246:Lysophospholipids; C060504:dihydrosphingosine 1-phosphate; C060506:sphingosine 1-phosphate; C097760:N-palmitoylsphingosine; D013110:Sphingosine
keywords: HCC; S1P; biomarker; dihydroceramide; sphingolipid