Induction of autotaxin by the Epstein-Barr virus promotes the growth and survival of Hodgkin lymphoma cells.
A proportion of patients with Hodgkin lymphoma carry Epstein-Barr virus (EBV), an oncogenic herpesvirus, in their tumor cells. Although it is generally assumed that EBV contributes to the malignant phenotype of Hodgkin lymphoma cells, direct evidence in support of this is lacking. Here we show that EBV infection of Hodgkin lymphoma cells results in the induction of autotaxin, a secreted tumor-associated factor with lysophospholipase-D activity. Up-regulation of autotaxin increased the generation of lysophosphatidic acid (LPA) and led to the enhanced growth and survival of Hodgkin lymphoma cells, whereas specific down-regulation of autotaxin decreased LPA levels and reduced cell growth and viability. In lymphoma tissues, autotaxin expression was mainly restricted to CD30+ anaplastic large-cell lymphomas and Hodgkin lymphoma; in the latter, high levels of autotaxin were strongly associated with EBV positivity (P = .006). Our results identify the induction of autotaxin and the subsequent generation of LPA as key molecular events that mediate the EBV-induced growth and survival of Hodgkin lymphoma cells and suggest that this pathway may provide opportunities for novel therapeutic intervention.
Baumforth
Karl R N
KR
CRUK Institute for Cancer Studies, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.
Flavell
Joanne R
JR
Reynolds
Gary M
GM
Davies
Gillian
G
Pettit
Trevor R
TR
Wei
Wenbin
W
Morgan
Susan
S
Stankovic
Tanya
T
Kishi
Yasuhiro
Y
Arai
Hiroyuki
H
Nowakova
Marketa
M
Pratt
Guy
G
Aoki
Junken
J
Wakelam
Michael J O
MJ
Young
Lawrence S
LS
Murray
Paul G
PG
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D020031:Epstein-Barr Virus Infections / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006689:Hodgkin Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D006801:Humans; D008246:Lysophospholipids / Q000096:biosynthesis; D009097:Multienzyme Complexes / Q000235:genetics*; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D015854:Up-Regulation; D000099189:Lysophospholipase D
D005956:Glucose-6-Phosphate Isomerase; D006023:Glycoproteins; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid