Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma.

Abstract	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.
Authors	Yang Liu, Phong Quang, Esteban Braggio, Hai Ngo, Gayane Badalian-Very, Ludmila Flores, Yong Zhang, Antonio Sacco, Patricia Maiso, Abdel Kareem Azab, Feda Azab, Ruben Carrasco, Barrett J Rollins, Aldo M Roccaro, Irene M Ghobrial
Journal	PloS one (PLoS One) Vol. 8 Issue 6 Pg. e66982 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID	23785514 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Apoptosis Regulatory Proteins BBC3 protein, human Glucocorticoid-Induced TNFR-Related Protein NF-kappa B Proto-Oncogene Proteins TNFRSF18 protein, human Tumor Suppressor Proteins Proto-Oncogene Proteins p21(ras)
Topics	Animals Apoptosis Regulatory Proteins (genetics, metabolism) Cell Line, Tumor Cell Proliferation CpG Islands DNA Methylation Disease Progression Gene Expression Regulation, Neoplastic Glucocorticoid-Induced TNFR-Related Protein (genetics, metabolism) Humans Mice Models, Biological Multiple Myeloma (genetics, metabolism, mortality) NF-kappa B (metabolism) Prognosis Promoter Regions, Genetic Proto-Oncogene Proteins (genetics, metabolism) Proto-Oncogene Proteins p21(ras) (genetics, metabolism) Signal Transduction Tumor Suppressor Proteins (genetics, metabolism)

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