Aberrant Expression of the S1P Regulating Enzymes, SPHK1 and SGPL1, Contributes to a Migratory Phenotype in OSCC Mediated Through S1PR2

Sci Rep. 2016 May 10;6:25650. doi: 10.1038/srep25650.

Abstract

Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde-Lyases / genetics*
  • Aldehyde-Lyases / metabolism
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics*
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cisplatin / pharmacology
  • Drug Synergism
  • Female
  • Fingolimod Hydrochloride / pharmacology
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Kaplan-Meier Estimate
  • Lysophospholipids / metabolism
  • Lysophospholipids / pharmacology
  • Male
  • Middle Aged
  • Mouth Neoplasms / genetics*
  • Mouth Neoplasms / metabolism
  • Mouth Neoplasms / pathology
  • Phenotype
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Receptors, Lysosphingolipid / genetics*
  • Receptors, Lysosphingolipid / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Sphingosine-1-Phosphate Receptors

Substances

  • Antineoplastic Agents
  • Immunosuppressive Agents
  • Lysophospholipids
  • Receptors, Lysosphingolipid
  • S1PR2 protein, human
  • Sphingosine-1-Phosphate Receptors
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Aldehyde-Lyases
  • SGPL1 protein, human
  • Fingolimod Hydrochloride
  • Sphingosine
  • Cisplatin