Leukotriene A4 hydrolase expression in PEL cells is regulated at the transcriptional level and leads to increased leukotriene B4 production.
Primary effusion lymphoma (PEL) is a herpesvirus-8-associated lymphoproliferative disease characterized by migration of tumor cells to serous body cavities. PEL cells originate from postgerminal center B cells and share a remarkable alteration in B cell transcription factor expression and/or activation with classical Hodgkin's disease cells. Comparative analysis of gene expression by cDNA microarray of BCBL-1 cells (PEL), L-428 (classical Hodgkin's disease), and BJAB cells revealed a subset of genes that were differentially expressed in BCBL-1 cells. Among these, four genes involved in cell migration and chemotaxis were strongly up-regulated in PEL cells: leukotriene A4 (LTA4) hydrolase (LTA4H), IL-16, thrombospondin-1 (TSP-1), and selectin-P ligand (PSGL-1). Up-regulation of LTA4H was investigated at the transcriptional level. Full-length LTA4H promoter exhibited 50% higher activity in BCBL-1 cells than in BJAB or L-428 cells. Deletion analysis of the LTA4H promoter revealed a positive cis-regulatory element active only in BCBL-1 cells in the promoter proximal region located between -76 and -40 bp. Formation of a specific DNA-protein complex in this region was confirmed by EMSA. Coculture of ionophore-stimulated primary neutrophils with BCBL-1 cells leads to an increased production of LTB4 compared with coculture with BJAB and L-428 cells as measured by enzyme immunoassay, demonstrating the functional significance of LTA4H up-regulation.
Arguello
Meztli
M
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Montreal, Quebec, Canada.
Paz
Suzanne
S
Hernandez
Eduardo
E
Corriveau-Bourque
Catherine
C
Fawaz
Lama M
LM
Hiscott
John
J
Lin
Rongtuan
R
D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics; D004851:Epoxide Hydrolases / Q000096:biosynthesis* / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D019410:Interleukin-16 / Q000502:physiology; D007975:Leukotriene B4 / Q000096:biosynthesis*; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
D019410:Interleukin-16; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D012333:RNA, Messenger; D019700:Thrombospondin 1; D007975:Leukotriene B4; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase