Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Neoplasia. 2013 Aug;15(8):888-97. doi: 10.1593/neo.13608.
Tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD) is an important adaptor in TNFR1 signaling and has an essential role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and survival signaling. Increased expression of TRADD is sufficient to activate NF-κB. Recent studies have highlighted the importance of NF-κB activation as a key pathogenic mechanism in glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults.We examined the expression of TRADD by immunohistochemistry (IHC) and find that TRADD is commonly expressed at high levels in GBM and is detected in both cytoplasmic and nuclear distribution. Cytoplasmic IHC TRADD scoring is significantly associated with worse progression-free survival (PFS) both in univariate and multivariate analysis but is not associated with overall survival (n = 43 GBMs). PFS is a marker for responsiveness to treatment. We propose that TRADD-mediated NF-κB activation confers chemoresistance and thus a worse PFS in GBM. Consistent with the effect on PFS, silencing TRADD in glioma cells results in decreased NF-κB activity, decreased proliferation of cells, and increased sensitivity to temozolomide. TRADD expression is common in glioma-initiating cells. Importantly, silencing TRADD in GBM-initiating stem cell cultures results in decreased viability of stem cells, suggesting that TRADD may be required for maintenance of GBM stem cell populations. Thus, our study suggests that increased expression of cytoplasmic TRADD is both an important biomarker and a key driver of NF-κB activation in GBM and supports an oncogenic role for TRADD in GBM.
肿瘤坏死因子受体 1（TNFR1）相关死亡结构域蛋白（TRADD）是 TNFR1 信号转导中的重要衔接蛋白，在核因子 kappa 轻链增强子的激活 B 细胞（NF-κB）激活和存活信号中具有重要作用。TRADD 的表达增加足以激活 NF-κB。最近的研究强调了 NF-κB 激活作为多形性胶质母细胞瘤（GBM）的关键致病机制的重要性，GBM 是成人中最常见的原发性恶性脑肿瘤。我们通过免疫组织化学（IHC）检查了 TRADD 的表达，发现 TRADD 在 GBM 中通常高表达，并在细胞质和核分布中均有检测到。细胞质 IHC TRADD 评分在单变量和多变量分析中均与较差的无进展生存期（PFS）显著相关，但与总生存期（n = 43 例 GBM）无关。PFS 是对治疗反应性的标志物。我们提出，TRADD 介导的 NF-κB 激活赋予了 GBM 化疗耐药性，从而导致较差的 PFS。与对 PFS 的影响一致，沉默神经胶质瘤细胞中的 TRADD 会导致 NF-κB 活性降低、细胞增殖减少和对替莫唑胺的敏感性增加。TRADD 表达在神经胶质瘤起始细胞中很常见。重要的是，沉默 GBM 起始干细胞培养物中的 TRADD 会导致干细胞活力降低，这表明 TRADD 可能是维持 GBM 干细胞群体所必需的。因此，我们的研究表明，细胞质 TRADD 的表达增加既是 GBM 中 NF-κB 激活的重要生物标志物，也是关键驱动因素，并支持 TRADD 在 GBM 中的致癌作用。
