Table_12_LncRNA-FAM66C Was Identified as a Key Regulator for Modulating Tumor Microenvironment and Hypoxia-Related Pathways in Glioblastoma.XLSX

Although the role of hypoxia has been greatly explored and unveiled in glioblastoma (GBM), the mechanism of hypoxia-related long non-coding (lnc) RNAs has not been clearly understood. This study aims to reveal the crosstalk among hypoxia-related lncRNAs, tumor microenvironment (TME), and tumorigenesis for GBM. Gene expression profiles of GBM patients were used as a basis for identifying hypoxia-related lncRNAs. Unsupervised consensus clustering was conducted for classifying samples into different molecular subtypes. Gene set enrichment analysis (GSEA) was performed to analyze the enrichment of a series of genes or gene signatures. Three molecular subtypes were constructed based on eight identified hypoxia-related lncRNAs. Oncogenic pathways, such as epithelial mesenchymal transition (EMT), tumor necrosis factor-α (TNF-α) signaling, angiogenesis, hypoxia, P53 signaling, and glycolysis pathways, were significantly enriched in C1 subtype with poor overall survival. C1 subtype showed high immune infiltration and high expression of immune checkpoints. Furthermore, we identified 10 transcription factors (TFs) that were highly correlated with lncRNA-FAM66C. Three key lncRNAs (ADAMTS9-AS2, LINC00968, and LUCAT1) were screened as prognostic biomarkers for GBM. This study shed light on the important role of hypoxia-related lncRNAs for TME modulation and tumorigenesis in GBM. The eight identified hypoxia-related lncRNAs, especially FAM66C may serve as key regulators involving in hypoxia-related pathways.

尽管缺氧在胶质母细胞瘤（glioblastoma, GBM）中的作用已得到广泛探索与阐明，但缺氧相关长链非编码（long non-coding, lnc）RNA的作用机制仍未完全明确。本研究旨在阐明胶质母细胞瘤中缺氧相关长链非编码RNA、肿瘤微环境（tumor microenvironment, TME）与肿瘤发生之间的串扰机制。研究以胶质母细胞瘤患者的基因表达谱为基础，筛选鉴定缺氧相关长链非编码RNA；通过无监督共识聚类法将样本划分为不同分子亚型，并采用基因集富集分析（gene set enrichment analysis, GSEA）分析一系列基因或基因特征的富集情况。基于筛选得到的8个缺氧相关长链非编码RNA，本研究构建了三种分子亚型。上皮间质转化（epithelial mesenchymal transition, EMT）、肿瘤坏死因子-α（tumor necrosis factor-α, TNF-α）信号通路、血管生成、缺氧、P53信号通路及糖酵解通路等致癌通路，在总体生存率较差的C1亚型中显著富集；该亚型同时呈现较高的免疫浸润水平与免疫检查点高表达特征。此外，本研究鉴定出10个与lncRNA-FAM66C高度相关的转录因子（transcription factors, TFs），并筛选出ADAMTS9-AS2、LINC00968与LUCAT1这3个关键长链非编码RNA，作为胶质母细胞瘤的预后生物标志物。本研究揭示了缺氧相关长链非编码RNA在胶质母细胞瘤肿瘤微环境调控与肿瘤发生过程中的重要作用；本次筛选得到的8个缺氧相关长链非编码RNA，尤其是FAM66C，可作为缺氧相关通路的关键调控因子。