Novel Tumor Suppressor Function of Glucocorticoid-Induced TNF Receptor GITR in Multiple Myeloma
Novel Tumor Suppressor Function of Glucocorticoid-Induced TNF Receptor GITR in Multiple Myeloma
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DOI：
10.1371/journal.pone.0066982
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发表时间：
2013-06-13
期刊：
影响因子：
3.7
通讯作者：
Ghobrial, Irene M.
中科院分区：
文献类型：
--
作者：
Liu, Yang;Phong Quang;Ghobrial, Irene M.
糖皮质激素诱导的 TNF 受体 (GITR) 在调节免疫反应和炎症方面发挥着至关重要的作用，但 GITR 在人类癌症中的作用却知之甚少。在这项研究中，我们证明了 GITR 在多发性骨髓瘤 (MM) 肿瘤进展过程中通过启动子 CpG 岛甲基化失活，介导原代 MM 浆细胞和 MM 细胞系中的基因沉默。 GITR缺陷MM细胞中GITR表达的恢复导致体外和体内MM增殖的抑制以及细胞凋亡的诱导。 p21 和 PUMA（p53 的两个直接下游靶标）的诱导存在以及 GITR 过表达 MM 细胞中 NF-κ B 的调节支持了这些发现。此外，克隆浆细胞中 GITR 的不平衡表达与 MM 疾病进展、不良预后和生存相关。这些发现为 GITR 在 MM 发病机制和疾病进展中的关键作用提供了新的见解。
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-kappa B 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.