Wang Yanfang, Xin Shan, Zhang Kai, Shi Run, Bao Xuanwen
Ludwig-Maximilians-Universität München (LMU), 80539 Munich, Germany.
Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310016 Hangzhou, China.
J Oncol. 2019 Feb 3;2019:1785042. doi: 10.1155/2019/1785042. eCollection 2019.
Gliomas are infiltrative neoplasms of a highly invasive nature. Different stages of gliomas feature distinct genomic, genetic, and epigenetic changes. The long noncoding RNA Growth Arrest Specific Transcript 5 (GAS5) is an identified tumour suppressor involved in several cancers. However, the underlying roles of the GAS5 gene in lower-grade glioma (LGG) patients are not clear.
Via bioinformatic analysis based on TCGA-LGG and TCGA-GBM data, we explored the mechanisms of GAS5 expression in LGG (grades II and III) and high-grade glioma (glioblastoma multiforme, grade IV). The log-rank test and multivariate Cox analysis were performed to find the association between GAS5 and overall survival (OS) in LGG patients. Weighted gene coexpression network analysis (WGCNA) and RNA-Seq analysis were applied to find the key gene network associated with GAS5.
We found that GAS5 expression was downregulated in both LGG and glioblastoma multiforme (GBM) compared with normal brain tissue. Low methylation in the GAS5 promoter region was detected in both LGG and GBM tissues. The amplification type was the predominant type of GAS5 gene alteration in both LGG and GBM. High GAS5 expression was more associated with long overall survival (OS) in LGG patients than in GBM patients. The multivariate survival analysis of GAS5 and clinical and molecular characteristics in LGG patients further confirmed the association between GAS5 and OS in LGG patients. We then developed a nomogram for clinical use. WGCNA and RNA-Seq analysis indicated that ribosomal biogenesis and translation initiation were the predominant events regulated by GAS5 in LGG patients.
Taken together, these results demonstrate that GAS5 expression is associated with OS in LGG patients and that its underlying roles involve the regulation of ribosomal biogenesis and translation initiation, which may aid in identifying a new target for the treatment of LGG.
胶质瘤是具有高度侵袭性的浸润性肿瘤。胶质瘤的不同阶段具有不同的基因组、遗传和表观遗传变化。长链非编码RNA生长停滞特异性转录本5（GAS5）是一种已确定的参与多种癌症的肿瘤抑制因子。然而，GAS5基因在低级别胶质瘤（LGG）患者中的潜在作用尚不清楚。
通过基于TCGA-LGG和TCGA-GBM数据的生物信息学分析，我们探讨了GAS5在LGG（二级和三级）和高级别胶质瘤（多形性胶质母细胞瘤，四级）中的表达机制。进行对数秩检验和多变量Cox分析以发现GAS5与LGG患者总生存期（OS）之间的关联。应用加权基因共表达网络分析（WGCNA）和RNA测序分析来寻找与GAS5相关的关键基因网络。
我们发现，与正常脑组织相比，LGG和多形性胶质母细胞瘤（GBM）中GAS5的表达均下调。在LGG和GBM组织中均检测到GAS5启动子区域的低甲基化。扩增型是LGG和GBM中GAS5基因改变的主要类型。与GBM患者相比，LGG患者中高GAS5表达与更长的总生存期（OS）更相关。对LGG患者中GAS5与临床和分子特征的多变量生存分析进一步证实了GAS5与LGG患者OS之间的关联。然后我们开发了一个用于临床的列线图。WGCNA和RNA测序分析表明，核糖体生物发生和翻译起始是LGG患者中受GAS5调控的主要事件。
综上所述，这些结果表明GAS5表达与LGG患者的OS相关，其潜在作用涉及核糖体生物发生和翻译起始的调控，这可能有助于确定LGG治疗的新靶点。
