Elevated Fras1-related extracellular matrix 3 in isocitrate dehydrogenase 1-mutant astrocytoma World Health Organization grade 4 predicts favorable prognosis in glioma: A bioinformatic and experimental analysis

Abstract

Background and Aim: World Health Organization (WHO) grade 4 glioma is a malignancy of the central nervous system characterized by refractoriness to treatment and a high mortality rate. Isocitrate dehydrogenase (IDH) mutation is a crucial molecular event for the classification of glioma and associated with prognosis and exploring genetic and molecular differences between IDH mutant and wildtype glioma is crucial. The aim of this study was to investigate the prognostic gene between IDH mutant and wildtype WHO grade 4 glioma and its functional significance. Materials and Methods: The mRNA expression profile data of WHO grade 4 glioma were downloaded from the Gene Expression Omnibus and Chinese Glioma Genome Atlas databases. Bioinformatic analysis was performed to identify the differentially expressed genes between IDH1-mutant and wildtype WHO grade 4 glioma. Survival analysis, functional enrichment analysis, immune cell infiltration evaluation, and in vitro experimental validation were conducted to evaluate the prognostic and functional significance of Fras1-related extracellular matrix 3 (FREM3). This study was approved by the Institutional Ethics Committee of Xinqiao Hospital, Third Military Medical University (approval No. 2021-Y068-01). Results: Elevated expression of FREM3 in IDH1-mutant WHO grade 4 astrocytoma predicted favorable prognosis in glioma. FREM3 was negatively associated with epithelial–mesenchymal transition (EMT), angiogenesis, and hypoxia; notably, low expression of FREM3 was associated with a higher degree of immune cell infiltration. In vitro experiments demonstrated that high FREM3 expression might attenuate the process of EMT and cellular proliferation in glioma. Conclusions: The gene FREM3 plays a major role in IDH1-mutant WHO grade 4 glioma and elevated FREM3 predicts a favorable prognosis of glioma. Further investigation on FREM3 is warranted to elucidate the mechanisms underlying the malignant evolution of glioma.