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Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV-associated nasopharyngeal carcinoma

Significance statement

Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) is remarkably prevalent in South East Asia and Southern China. Late presentation is the major challenge of nasopharyngeal carcinoma management and due to the location of the tumor at the base of the skull, and in close proximity to many vital structures, most survivors of nasopharyngeal carcinoma have impaired health-related quality of life. Unfortunately our current understanding of the molecular basis of nasopharyngeal carcinoma is still inadequate to inform any personalized treatment strategies for patients. Our present study has shown for the first time that EBV infection contributes to an aberrantly activated lysophosphatidic acid (LPA) signaling pathway in nasopharyngeal carcinoma. LPA is a bioactive lipid molecule that functions as a tumor promoter. Apart from LPA itself, the enzyme that produces LPA (ATX) and receptors that LPA binds to (LPAR), are all promising cancer therapeutic targets. In this study, we show that nasopharyngeal carcinoma cells express ATX which in turn will produce LPA that exerts oncogenic effects by enhancing nasopharyngeal carcinoma cell migration via the down-regulation of LPA receptor 5. We also show that LPA can inhibit the activity of EBV-specific cytotoxic T cells (CTL), suggesting that LPA might contribute to the obstacle in adoptive EBV-specific CTL immunotherapy. The development of therapeutic LPA signaling antagonists has blossomed in recent years and this provides a compelling justification to stratify nasopharyngeal carcinoma patients for LPA-based targeted therapies.

Figure legend: A proposed model of LPA signaling in NPC. nasopharyngeal carcinoma cells express ATX which converts LPC to LPA. LPA exerts two different functional roles; first, LPA inhibits cytotoxic T cell function and second, that it enhances the migration of nasopharyngeal carcinoma cells via the down-regulation of LPAR5.

Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV-associated nasopharyngeal carcinoma. Global Medical Discovery

 

 

 

 

 

 

 

 

 

Journal Reference

Yap LF1,2,*, Velapasamy S1, Lee HM1, Thavaraj S3, Rajadurai P4, Wei W2, Vrzalikova K2, Ibrahim MH2, Khoo AS5, Tsao SW6, Ian C Paterson IC1, TaylorcGS2, Dawson CW2 and Murray PG2,*. J Pathol. 2015;235(3):456-65.

  1. Department of Oral Biology & Biomedical Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
  2. School of Cancer Sciences, University of Birmingham, Birmingham, UK.
  3. Clinical and Diagnostic Sciences, King’s College London Dental Institute, London, UK.
  4. Subang Jaya Medical Centre, Subang Jaya, Malaysia.
  5. Molecular Pathology Unit, Institute for Medical Research, Kuala Lumpur, Malaysia.
  6. Department of Anatomy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.

Abstract

Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of nasopharyngeal carcinoma. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor5 (LPAR5), is down-regulated in primary nasopharyngeal carcinoma tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in nasopharyngeal carcinoma and identify LPA signalling as a potential therapeutic target in this disease.

Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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