Integrated Transcriptome Analyses and Experimental Verifications of Mesenchymal-Associated TNFRSF1A as a Diagnostic and Prognostic Biomarker in Gliomas

Abstract

Gliomas are the most prevalent malignant primary brain tumors with poor outcome, and four different molecular subtypes (Mesenchymal, Proneural, Neural, and Classical) are popularly applied in scientific researches and clinics of gliomas. Public databases contain an abundant genome-wide resource to explore the potential biomarker and molecular mechanisms using the informatics analysis. The aim of this study was to discover the potential biomarker and investigate its effect in gliomas. Weighted gene co-expression network analysis (WGCNA) was used to construct the co-expression modules and explore the biomarker among the dataset CGGA mRNAseq_693 carrying 693 glioma samples. Functional annotations, ROC, correlation, survival, univariate, and multivariate Cox regression analyses were implemented to investigate the functional effect in gliomas, and molecular experiments in vitro were performed to study the biological effect on glioma pathogenesis. The brown module was found to be strongly related to WHO grade of gliomas, and KEGG pathway analysis demonstrated that TNFRSF1A was enriched in MAPK signaling pathway and TNF signaling pathway. Overexpressed TNFRSF1A was strongly related to clinical features such as WHO grade, and functioned as an independent poor prognostic predictor of glioma patients. Notably, TNFRSF1A was preferentially upregulated in the Mesenchymal subtype gliomas (Mesenchymal-associated). Knockdown of TNFRSF1A inhibited proliferation and migration of glioma cell lines in vitro. Our findings provide a further understanding of the progression of gliomas, and Mesenchymal-associated TNFRSF1A might be a promising target of diagnosis, therapy, and prognosis of gliomas.

Low expression of CDHR1 is an independent unfavorable prognostic factor in glioma

“…Consistent with the high expression in GBM subtype, previous reports suggested that CCDC109B [27], CD58 [28], CLIC1 [29], EFEMP2 [30], EMP3 [31][32][33], LAMC1 [34], LGALS1 [35], PDLIM1 [36] and TNFRSF1A [37,38] were all bad prognostic factors in glioma, as were summarized in Fig. 2A.…”

The Expression of PPAR Pathway-Related Genes Can Better Predict the Prognosis of Patients with Colon Adenocarcinoma

“…Knockdown of TNFRSF1A inhibited the proliferation and migration of glioma cell lines in vitro. These findings suggest that TNFRSF1A may be a promising biomarker for the diagnosis, treatment, and prognosis of mesenchymal subtype gliomas [ 41 ]. As a result of the disruption of REN tumor suppression function shown in human medulloblastoma, the issue of whether this gene is involved in the formation of cerebellar GCPs has been raised.…”

Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy

“…Based on our results, guadecitabine induced TNFRSF10A (in the three histotypes) and TNFRSF1B (in sarcomatoid and biphasic cell lines), sustaining cell death signals and apoptosis, but also CD70 (in seven mixed cell lines), which could potentially enhance the generation of cytolytic T cells and contribute to T cell activation. Moreover, a recent study reports the overexpression of the mesenchymal-associated TNFRSF1A to be strongly related to poor prognosis, and its knockdown to inhibit proliferation and migration of tumor cell lines in vitro [ 45 ]; also, it seems to induce the production of IL-17 by CD4+ T cells, recruiting myeloid cells and supporting tumor growth [ 46 ]. We registered the down-regulation of TNFRSF1A, especially in sarcomatoid and biphasic cell lines; this could be a mechanism, induced by guadecitabine, to impair tumor progression and to avoid the recruitment of immunosuppressive cells, that act as a barrier to cancer immunotherapy, also taking into consideration the down-regulation of the expression of IL17A-specific mRNA observed in the aforementioned phenotypes.…”