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.
Highlights
Tumor Necrosis Factor receptor superfamily members (TNFRSFs) play an important role in immune responses and inflammatory reactions [1,2,3,4,5]
We evaluated the expression of TNFRSFs in primary MM cells by analyzing GEO dataset GSE2658 and found that 7 members of the TNFRSF family includingTNFFSF18 (GITR), TNFRSF11A, TNFRSF9, TNFRSF19, TNFRSF8, TNFRSF21 and TNFRSF11B exhibited lower expression levels in MM cells compared to their normal cellular counterpart (Figure S1a)
We investigated the mechanisms responsible for down-regulation of TNFRSFs members; and profiled DNA methylation status of the promoter CpG islands (CGI) of the related genes using Methylated DNA immunoprecipitation (MeDIP) assay in 5 MM cell lines
Summary
Tumor Necrosis Factor receptor superfamily members (TNFRSFs) play an important role in immune responses and inflammatory reactions [1,2,3,4,5]. Other members of the family such as APRIL (TNFRSF13B) and BAFF (TNFRSF17) were shown to be involved in the protection of MM cells from apoptosis via NF-κB activation [9], while loss-offunction mutations of Fas antigen (TNFRSF6) could inhibit Fas ligand induced apoptosis in MM cells [10]. These studies suggest that TNFRSFs could play multiple roles in the pathogenesis of MM. The role of GITR as a direct regulator of tumor progression in MM has not been previously described
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