Department of Molecular & Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
PLoS One. 2013;8(2):e57489. doi: 10.1371/journal.pone.0057489. Epub 2013 Feb 25.
High-grade gliomas, such as glioblastomas (GBMs), are very aggressive, invasive brain tumors with low patient survival rates. The recent identification of distinct glioma tumor subtypes offers the potential for understanding disease pathogenesis, responses to treatment and identification of molecular targets for personalized cancer therapies. However, the key alterations that drive tumorigenesis within each subtype are still poorly understood. Although aberrant NF-κB activity has been implicated in glioma, the roles of specific members of this protein family in tumorigenesis and pathogenesis have not been elucidated. In this study, we show that the NF-κB protein RelB is expressed in a particularly aggressive mesenchymal subtype of glioma, and loss of RelB significantly attenuated glioma cell survival, motility and invasion. We find that RelB promotes the expression of mesenchymal genes including YKL-40, a marker of the MES glioma subtype. Additionally, RelB regulates expression of Olig2, a regulator of cancer stem cell proliferation and a candidate marker for the cell of origin in glioma. Furthermore, loss of RelB in glioma cells significantly diminished tumor growth in orthotopic mouse xenografts. The relevance of our studies for human disease was confirmed by analysis of a human GBM genome database, which revealed that high RelB expression strongly correlates with rapid tumor progression and poor patient survival rates. Thus, our findings demonstrate that RelB is an oncogenic driver of mesenchymal glioma tumor growth and invasion, highlighting the therapeutic potential of inhibiting the noncanonical NF-κB (RelB-mediated) pathway to treat these deadly tumors.
高级别神经胶质瘤，如胶质母细胞瘤（GBM），是侵袭性很强的脑部肿瘤，患者生存率低。最近发现的不同胶质瘤肿瘤亚型为了解疾病发病机制、对治疗的反应以及确定针对个性化癌症治疗的分子靶点提供了潜力。然而，每种亚型中驱动肿瘤发生的关键改变仍知之甚少。尽管异常 NF-κB 活性已被认为与神经胶质瘤有关，但该蛋白家族的特定成员在肿瘤发生和发病机制中的作用尚未阐明。在这项研究中，我们表明 NF-κB 蛋白 RelB 在胶质母细胞瘤中特别侵袭性的间质亚型中表达，并且 RelB 的缺失显著减弱了神经胶质瘤细胞的存活、迁移和侵袭。我们发现 RelB 促进了间质基因的表达，包括 YKL-40，这是 MES 胶质母细胞瘤亚型的标志物。此外，RelB 调节癌症干细胞增殖的调节因子 Olig2 的表达，是神经胶质瘤起源细胞的候选标志物。此外，RelB 在神经胶质瘤细胞中的缺失显著减少了原位小鼠异种移植肿瘤的生长。对人类 GBM 基因组数据库的分析证实了我们研究的相关性，该数据库显示高 RelB 表达与肿瘤快速进展和患者生存率低强烈相关。因此，我们的研究结果表明 RelB 是间充质神经胶质瘤肿瘤生长和侵袭的致癌驱动因素，突出了抑制非经典 NF-κB（RelB 介导）途径治疗这些致命肿瘤的治疗潜力。
