Department of Anatomy, Key Laboratory of Construction and Detection of Guangdong Province, Southern Medical University, Guangzhou, Guangdong, China.
PLoS One. 2012;7(9):e44559. doi: 10.1371/journal.pone.0044559. Epub 2012 Sep 12.
Previous reports indicate that the NIX/BNIP3L gene acts as a pro-apoptotic factor by interacting with BCL2 and BCL-XL, playing an important role in hypoxia-dependent cell death and acting as a tumor suppressor. However, many studies also showed that NIX is linked to a protective role and cell survival in cancer cells. Nuclear factor-κB (NF-κB) can attenuate apoptosis in human cancers in response to chemotherapeutic agents and ionizing radiation. We observed an absence of i-κBα (NF-κB activation inhibitor) expression, but a greater expression of Nix and p-NF-κB proteins in the Nix-wt U251 cells, which was not observed in the Nix-kn cells under hypoxic conditions. Using electrophoretic mobility shift assay (EMSA) and luciferase detection, the activation of NF-κB was detected only in the Nix-wt U251 cells with hypoxia. These data imply that Nix protein might play a role in the positive regulation of the NF-κB pathway. Moreover, 46 cases of glioma also showed high levels of Nix protein expression, which was always accompanied by high p-NF-κB expression. Patients with Nix (+) showed less tissue apoptosis behavior in glioblastoma (GBM), unlike that observed in the Nix-negative patients (-). The same apoptotic tendency was also identified in anaplastic astrocytoma (AA) groups, but not in astrocytoma (AS). On analyzing the Kaplan-Meier curve, better tumor-free survival was observed only in cases of astrocytoma, and not in AA and GBM. Thus, our study indicates that Nix protein might have multiple functions in regulating glioma behaviors. In the low-grade gliomas (astrocytoma) with low expression of NF-κB, the cell death-inducing function that occurs through a Bax mechanism might predominate and act as a tumor suppressor. While in the malignant gliomas (AA and GBM), with higher expression of the NIX gene and with activity of the NF-κB pathway, the oncogene function of Nix was predominant.
先前的报告表明，NIX/BNIP3L 基因通过与 BCL2 和 BCL-XL 相互作用，充当促凋亡因子，在缺氧依赖性细胞死亡中发挥重要作用，并作为肿瘤抑制因子。然而，许多研究也表明 NIX 与癌细胞中的保护作用和细胞存活有关。核因子-κB（NF-κB）可以减轻人类癌症对化疗药物和电离辐射的凋亡反应。我们观察到在 Nix-wt U251 细胞中缺乏 i-κBα（NF-κB 激活抑制剂）的表达，但在缺氧条件下的 Nix-kn 细胞中未观察到 Nix 和 p-NF-κB 蛋白的表达增加。通过电泳迁移率变动分析（EMSA）和荧光素酶检测，仅在缺氧的 Nix-wt U251 细胞中检测到 NF-κB 的激活。这些数据表明 Nix 蛋白可能在 NF-κB 通路的正调控中发挥作用。此外，46 例胶质瘤也表现出 Nix 蛋白表达水平升高，这总是伴随着 p-NF-κB 的高表达。与 Nix 阴性患者（-）相比，Nix（+）患者的胶质母细胞瘤（GBM）组织凋亡行为较少。在间变性星形细胞瘤（AA）组中也发现了相同的凋亡趋势，但在星形细胞瘤（AS）中没有发现。在分析 Kaplan-Meier 曲线时，仅在星形细胞瘤中观察到更好的无肿瘤生存，而在 AA 和 GBM 中则没有。因此，我们的研究表明 Nix 蛋白在调节胶质瘤行为方面可能具有多种功能。在 NF-κB 低表达的低级别胶质瘤（星形细胞瘤）中，通过 Bax 机制发生的细胞死亡诱导功能可能占主导地位，并发挥肿瘤抑制因子的作用。而在恶性胶质瘤（AA 和 GBM）中，NIX 基因表达较高且 NF-κB 通路活性较高，Nix 的致癌基因功能占主导地位。
