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

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.