Prostaglandin E2 regulates B cell proliferation through a candidate tumor suppressor, Ptger4.
B cell receptor (BCR) signaling contributes to the pathogenesis of B cell malignancies, and most B cell lymphomas depend on BCR signals for survival. Identification of genes that restrain BCR-mediated proliferation is therefore an important goal toward improving the therapy of B cell lymphoma. Here, we identify Ptger4 as a negative feedback regulator of proliferation in response to BCR signals and show that its encoded EP4 receptor is a principal molecule conveying the growth-suppressive effect of prostaglandin E2 (PGE2). Stable knockdown of Ptger4 in B cell lymphoma markedly accelerated tumor spread in mice, whereas Ptger4 overexpression yielded significant protection. Mechanistically, we show that the intrinsic activity of Ptger4 and PGE2-EP4 signaling target a similar set of activating genes, and find Ptger4 to be significantly down-regulated in human B cell lymphoma. We postulate that Ptger4 functions in B cells as a candidate tumor suppressor whose activity is regulated by PGE2 in the microenvironment. These findings suggest that targeting EP4 receptor for prostaglandin may present a novel strategy for treatment of B cell malignancies.
Murn
Jernej
J
CEA, DSV, Institut de Radiobiologie Cellulaire et Moléculaire, Laboratoire d'Exploration Fonctionnelle des Génomes, Evry, France.
Alibert
Olivier
O
Wu
Ning
N
Tendil
Simon
S
Gidrol
Xavier
X
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D049109:Cell Proliferation; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000502:physiology; D012926:Social Control, Formal; D015996:Survival Rate
C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone