title: 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.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Phong
authors.initials: P
authors.lastname: Quang
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.forename: Hai
authors.initials: H
authors.lastname: Ngo
authors.forename: Gayane
authors.initials: G
authors.lastname: Badalian-Very
authors.forename: Ludmila
authors.initials: L
authors.lastname: Flores
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Ruben
authors.initials: R
authors.lastname: Carrasco
authors.forename: Barrett J
authors.initials: BJ
authors.lastname: Rollins
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D016328:NF-kappa B / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D053450:Glucocorticoid-Induced TNFR-Related Protein; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C491405:TNFRSF18 protein, human; D025521:Tumor Suppressor Proteins; D016283:Proto-Oncogene Proteins p21(ras)