TY - JOUR
T1 - Novel Tumor Suppressor Function of Glucocorticoid-Induced TNF Receptor GITR in Multiple Myeloma
AU - Liu, Yang
AU - Quang, Phong
AU - Braggio, Esteban
AU - Ngo, Hai
AU - Badalian-Very, Gayane
AU - Flores, Ludmila
AU - Zhang, Yong
AU - Sacco, Antonio
AU - Maiso, Patricia
AU - Azab, Abdel Kareem
AU - Azab, Feda
AU - Carrasco, Ruben
AU - Rollins, Barrett J.
AU - Roccaro, Aldo M.
AU - Ghobrial, Irene M.
PY - 2013/6/13
Y1 - 2013/6/13
N2 - Glucocorticoid-induced TNF receptor (GITR) plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM) through promoter CpG island methylation, mediating gene silencing in primary MM plasma cells and MM cell lines. Restoration of GITR expression in GITR deficient MM cells led to inhibition of MM proliferation in vitro and in vivo and induction of apoptosis. These findings were supported by the presence of induction of p21 and PUMA, two direct downstream targets of p53, together with modulation of NF-κB in GITR-overexpressing MM cells. Moreover, the unbalanced expression of GITR in clonal plasma cells correlated with MM disease progression, poor prognosis and survival. These findings provide novel insights into the pivotal role of GITR in MM pathogenesis and disease progression.
AB - Glucocorticoid-induced TNF receptor (GITR) plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM) through promoter CpG island methylation, mediating gene silencing in primary MM plasma cells and MM cell lines. Restoration of GITR expression in GITR deficient MM cells led to inhibition of MM proliferation in vitro and in vivo and induction of apoptosis. These findings were supported by the presence of induction of p21 and PUMA, two direct downstream targets of p53, together with modulation of NF-κB in GITR-overexpressing MM cells. Moreover, the unbalanced expression of GITR in clonal plasma cells correlated with MM disease progression, poor prognosis and survival. These findings provide novel insights into the pivotal role of GITR in MM pathogenesis and disease progression.
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U2 - 10.1371/journal.pone.0066982
DO - 10.1371/journal.pone.0066982
M3 - Article
C2 - 23785514
AN - SCOPUS:84879062784
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 6
M1 - e66982
ER -