Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, No.17 Changle Western Road, 710032 Xi'an, China.
Med Oncol. 2012 Jun;29(2):1272-9. doi: 10.1007/s12032-011-9835-x. Epub 2011 Feb 8.
Nuclear factor (NF)-kappa-B is a pleiotropic transcriptional regulator that plays important roles in cell differentiation, growth, tumorigenesis, and apoptosis. Constitutive NF-kappa-B is overexpressed and activated in various tumors, including gliomas. Here, we investigated the expression of NF-kappa-B inhibitor interacting ras-like protein 1 (κB-Ras1), which is one of the most important negative modulators of NF-kappa-B, and a well-known proliferation biomarker survivin protein. We performed immunohistochemistry and western blot analysis on 154 glioma specimens and 3 non-neoplastic brain parenchyma specimens. Immunohistochemistry showed a strong-to-weak range of κB-Ras1 staining with increasing pathologic grade of glioma (P = 0.000). Immunoreactivity scores of κB-Ras1 were 8.15 ± 0.72 in non-neoplastic brain parenchyma, 5.00 ± 0.29 in low-grade gliomas, 3.89 ± 0.30 in anaplasia astrocytomas, and 2.78 ± 0.25 in glioblastomas. In contrast, the immunoreactivity of survivin increased with pathological grade in gliomas. The immunohistochemical data were in line with the results from western blot analysis. Moreover, a non-parametric analysis revealed that the attenuated κB-Ras1 expression was correlated with elevated survivin expression, large tumor diameter, frequent intra-tumor necrosis, and worse overall survival. These results indicated that κB-Ras1 was down-regulated in gliomas compared to non-neoplastic brain parenchyma, and the expression was even lower in glioblastomas. In addition, multivariate analysis showed that κB-Ras1 expression and intra-tumor necrosis were two important prognostic factors identified by the Cox proportional hazards model. Taken together, our study suggests that glioma patients with lower κB-Ras1 expression have a worse prognosis, which is partly due to NF-kappa-B pathway-mediated aberrant proliferation of tumor cells.
核因子（NF）-kappa-B 是一种多效转录调节因子，在细胞分化、生长、肿瘤发生和凋亡中发挥重要作用。在包括神经胶质瘤在内的各种肿瘤中，组成型 NF-kappa-B 过表达和激活。在这里，我们研究了 NF-kappa-B 抑制剂相互作用的 Ras 样蛋白 1（κB-Ras1）的表达，κB-Ras1 是 NF-kappa-B 的最重要的负调节因子之一，也是众所周知的增殖生物标志物 survivin 蛋白。我们对 154 例神经胶质瘤标本和 3 例非肿瘤性脑实质标本进行了免疫组织化学和 Western blot 分析。免疫组织化学显示，κB-Ras1 的染色强度随神经胶质瘤病理分级的升高而逐渐减弱（P = 0.000）。非肿瘤性脑实质中 κB-Ras1 的免疫反应评分为 8.15 ± 0.72，低级别神经胶质瘤为 5.00 ± 0.29，间变性星形细胞瘤为 3.89 ± 0.30，胶质母细胞瘤为 2.78 ± 0.25。相反，survivin 的免疫反应性随着神经胶质瘤的病理分级而增加。免疫组化数据与 Western blot 分析结果一致。此外，非参数分析显示，κB-Ras1 表达的减弱与 survivin 表达的升高、肿瘤直径较大、肿瘤内频繁坏死以及总体生存较差有关。这些结果表明，与非肿瘤性脑实质相比，κB-Ras1 在神经胶质瘤中下调，并且在胶质母细胞瘤中表达更低。此外，多变量分析显示，κB-Ras1 表达和肿瘤内坏死是 Cox 比例风险模型确定的两个重要预后因素。综上所述，我们的研究表明，κB-Ras1 表达较低的神经胶质瘤患者预后较差，这部分是由于 NF-kappa-B 通路介导的肿瘤细胞异常增殖所致。
