Hu Tieyi, Xi Jiazhuang
Department of Neurology.
Department of Public Health, The People's Hospital of Dazu District Chongqing, Chongqing, People's Republic of China.
Onco Targets Ther. 2017 Nov 15;10:5463-5470. doi: 10.2147/OTT.S139243. eCollection 2017.
Malignant glioma is the second leading cause of cancer-related death worldwide, and is known to exhibit a high degree of heterogeneity in its deregulation of different oncogenic pathways. The molecular subclasses of human glioma are not well known. Thus, it is crucial to identify vital oncogenic pathways in glioma with significant relationships to patient survival.
In this study, we devised a bioinformatics strategy to map patterns of oncogenic pathway activation in glioma, from the Gene Expression Omnibus (GEO). Bioinformatics analysis revealed that 749 genes were differentially expressed and classified into different glioma grades.
Using gene expression signatures, we identified three oncogenic pathways (MAPK signaling pathway, Wnt signaling pathway, and ErbB signaling pathway) deregulated in the majority of human glioma. Following gene microarray analysis, the gene expression profile in the differential grade glioma was further validated by bioinformatic analyses, with coexpression network construction. Furthermore, we found that cytochrome c oxidase subunit Vb (COX5B), the terminal enzyme of the electron transport chain, was the central gene in a coexpression network that transfers electrons from reduced cytochrome c to oxygen and, in the process, generates an electrochemical gradient across the mitochondrial inner membrane. The expression level of COX5B was then detected in 87 glioma tissues as well as adjacent normal tissues using immunohistochemistry. We found that COX5B was significantly upregulated in 67 of 87 (77.0%) glioma and glioblastoma tissues, compared with adjacent tissue (<0.01). Furthermore, statistical analysis showed the COX5B expression level was significantly associated with clinical stage and lymph node status, while there were no correlations between COX5B expression and age or tumor size.
These data indicate that COX5B may be implicated in glioma pathogenesis and as a biomarker for identification of the pathological grade of glioma.
恶性胶质瘤是全球癌症相关死亡的第二大主要原因，已知其在不同致癌途径的失调方面表现出高度异质性。人类胶质瘤的分子亚类尚不清楚。因此，确定与患者生存有显著关系的胶质瘤重要致癌途径至关重要。
在本研究中，我们设计了一种生物信息学策略，以绘制来自基因表达综合数据库（GEO）的胶质瘤致癌途径激活模式。生物信息学分析显示，749个基因差异表达并分为不同的胶质瘤级别。
利用基因表达特征，我们确定了在大多数人类胶质瘤中失调的三种致癌途径（丝裂原活化蛋白激酶信号通路、Wnt信号通路和表皮生长因子受体信号通路）。基因芯片分析后，通过构建共表达网络的生物信息学分析进一步验证了不同级别胶质瘤中的基因表达谱。此外，我们发现细胞色素c氧化酶亚基Vb（COX5B），即电子传递链的末端酶，是共表达网络中的核心基因，该网络将电子从还原型细胞色素c转移到氧，并在此过程中在线粒体内膜上产生电化学梯度。然后使用免疫组织化学在87个胶质瘤组织以及相邻正常组织中检测COX5B的表达水平。我们发现，与相邻组织相比（<0.01），87个胶质瘤和胶质母细胞瘤组织中有67个（77.0%）的COX5B显著上调。此外，统计分析表明COX5B表达水平与临床分期和淋巴结状态显著相关，而COX5B表达与年龄或肿瘤大小之间无相关性。
这些数据表明，COX5B可能参与胶质瘤发病机制，并作为识别胶质瘤病理级别的生物标志物。
