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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation
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CpG Islands
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DNA Methylation
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Disease Progression
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Gene Expression Regulation, Neoplastic
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Glucocorticoid-Induced TNFR-Related Protein / genetics
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Glucocorticoid-Induced TNFR-Related Protein / metabolism*
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Humans
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Mice
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Models, Biological
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Multiple Myeloma / genetics
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Multiple Myeloma / metabolism*
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Multiple Myeloma / mortality
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NF-kappa B / metabolism
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Prognosis
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / metabolism
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Signal Transduction
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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Glucocorticoid-Induced TNFR-Related Protein
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NF-kappa B
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Proto-Oncogene Proteins
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TNFRSF18 protein, human
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Tumor Suppressor Proteins
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Proto-Oncogene Proteins p21(ras)