title: Oncogenic S1P signalling in EBV-associated nasopharyngeal carcinoma activates AKT and promotes cell migration through S1P receptor 3.
abstract: Undifferentiated nasopharyngeal carcinoma (NPC) is a cancer with high metastatic potential that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the functional contribution of sphingosine-1-phosphate (S1P) signalling to the pathogenesis of NPC. We show that EBV infection or ectopic expression of the EBV-encoded latent genes (EBNA1, LMP1, and LMP2A) can up-regulate sphingosine kinase 1 (SPHK1), the key enzyme that produces S1P, in NPC cell lines. Exogenous addition of S1P promotes the migration of NPC cells through the activation of AKT; shRNA knockdown of SPHK1 resulted in a reduction in the levels of activated AKT and inhibition of cell migration. We also show that S1P receptor 3 (S1PR3) mRNA is overexpressed in EBV-positive NPC patient-derived xenografts and a subset of primary NPC tissues, and that knockdown of S1PR3 suppressed the activation of AKT and the S1P-induced migration of NPC cells. Taken together, our data point to a central role for EBV in mediating the oncogenic effects of S1P in NPC and identify S1P signalling as a potential therapeutic target in this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Oral & Craniofacial Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Hui Min
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
authors.affiliation: Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham, UK.|Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.affiliation: School of Biomedical Sciences and Center for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Grace Tin Yun
authors.initials: GTY
authors.lastname: Chung
authors.affiliation: Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Maha Hafez
authors.initials: MH
authors.lastname: Ibrahim
authors.affiliation: Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Dawson
authors.affiliation: Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Murray
authors.affiliation: Department of Oral & Craniofacial Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Paterson
authors.affiliation: Department of Oral & Craniofacial Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Lee Fah
authors.identifier: 0000-0002-6815-3607
authors.initials: LF
authors.lastname: Yap
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002277:Carcinoma; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D000081025:Sphingosine-1-Phosphate Receptors; D015854:Up-Regulation
chemical_list: D008246:Lysophospholipids; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C577483:sphingosine-1-phosphate receptor-3, human; C060506:sphingosine 1-phosphate; D051058:Oncogene Protein v-akt; D013110:Sphingosine
keywords: Epstein-Barr virus; S1P receptor; nasopharyngeal carcinoma; sphingosine-1-phosphate