Oncogenic S1P signalling in EBV-associated nasopharyngeal carcinoma activates AKT and promotes cell migration through S1P receptor 3

Research output: Contribution to journalArticle

Authors

  • Hui Min Lee
  • Kwok-Wai Lo
  • Sai Wah Tsao
  • Grace Tin Yun Chung
  • Maha Hafez Ibrahim
  • Ian C Paterson
  • Lee Fah Yap

Colleges, School and Institutes

External organisations

  • Department of Oral and Craniofacial Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia.
  • Department of Anatomical & 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.
  • Institute of Cancer and Genomic Medicine, University of Birmingham, Birmingham, United Kingdom.
  • School of Biomedical Sciences and Center for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.

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 over-expressed 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.

Details

Original languageEnglish
JournalJournal of Pathology
Early online date27 Feb 2017
Publication statusE-pub ahead of print - 27 Feb 2017

Keywords

  • Nasopharyngeal carcinoma, Epstein-Barr virus , Sphingosine-1-phosphate , S1P receptor