title: Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2.
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.
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research &Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors.forename: Sathya Narayanan
authors.initials: SN
authors.lastname: Patmanathan
authors.affiliation: Dept of Molecular Genetics, The Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, United Kingdom.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Johnson
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research &Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors.forename: Sook Ling
authors.initials: SL
authors.lastname: Lai
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research &Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors.forename: Suthashini
authors.initials: S
authors.lastname: Panja Bernam
authors.affiliation: Department of Oral surgery, Edinburgh Postgraduate Dental Institute, University of Edinburgh, Edinburgh, EH3 9HA, United Kingdom.
authors.forename: Victor
authors.initials: V
authors.lastname: Lopes
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Maha Hafez
authors.initials: MH
authors.lastname: Ibrahim
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117456 Singapore.
authors.forename: Federico
authors.initials: F
authors.lastname: Torta
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117456 Singapore.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Narayanaswamy
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117456 Singapore.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117456 Singapore.
authors.forename: Deron R
authors.initials: DR
authors.lastname: Herr
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research &Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors.forename: Lee Fah
authors.initials: LF
authors.lastname: Yap
authors.affiliation: Department of Oral Biology and Biomedical Sciences and Oral Cancer Research &Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Paterson
mesh_terms: D000446:Aldehyde-Lyases / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase
chemical_list: D000446:Aldehyde-Lyases; D000970:Antineoplastic Agents; D002945:Cisplatin; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C477522:S1PR2 protein, human; C060506:sphingosine 1-phosphate; C000623292:SGPL1 protein, human