sphingosine-1-phosphate and Mouth-Neoplasms

We have determined the gene expression of sphingosine-1-phosphate (S1P) metabolizing enzymes (SphK1, SphK2, SGPL1, SGPP1, SGPP2, PPAP2A, PPAP2B, and PPAP2C) by quantitative real-time polymerase chain reaction in tumor tissues and adjacent normal tissues of 50 oral squamous cell carcinoma (OSCC) patients. Expression of SphK1 and SGPP1 genes was up-regulated significantly in 70% and 75% OSCC tumors respectively. Importantly, expression of SphK2 and PPAP2B was down-regulated in the tumor tissues of 70% OSCC patients. Expression of SphK2 and PPAP2B negatively correlated with tumor-node-metastasis (TNM) staging and tumor volume respectively. Furthermore, LPP1 is an independent predictor of TNM staging and lymph node ratio.

Topics: Adult; Aged; Female; Humans; Lip Neoplasms; Lysophospholipids; Male; Membrane Proteins; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Phosphatidate Phosphatase; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Real-Time Polymerase Chain Reaction; RNA, Messenger; Sphingosine; Tongue Neoplasms; Young Adult

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.

Topics: Aldehyde-Lyases; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Cell Movement; Cell Survival; Cisplatin; Drug Synergism; Female; Fingolimod Hydrochloride; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Lysophospholipids; Male; Middle Aged; Mouth Neoplasms; Phenotype; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors