A Cuproptosis-Related lncRNA Signature Predicts Prognosis and Shapes the Immune Landscape in Primary Lower-Grade Glioma

Glioma represents the most prevalent intracranial neoplasms. Lower-grade gliomas (LGGs) are an important subtype of glioma, but the risk stratification of LGG has not been fully elucidated. As a recently recognized form of programmed cell death, Cuproptosis is intimately tied to Mitochondrial Metabolism. Moreover, investigations have revealed that Cuproptosis has been implicated in tumor initiation and progression. Long noncoding RNAs (lncRNAs) are engaged in diverse biological processes and connected with the malignant phenotype of gliomas. However, the significance of cuproptosis-related lncRNAs (CRLs) in LGG development remains not fully elucidated. In this work, 963 CRLs were identified using correlation analysis, and a prognostic signature was constructed based on LASSO and multivariate COX regression analyses. This signature comprised four CRLs: AC002456.1, tumor protein p63 regulated 1-antisense RNA 1 (TPRG1-AS1), AC098851.1, and LYR motif containing 4-antisense RNA 1 (LYRM4-AS1). According to the CRL-based signature, LGG patients were classified into distinct risk groups. To investigate the involvement of biological processes in each LGG sample, we performed gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) comparing the different risk stratifications. Subsequently, the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression (ESTIMATE) data and the tumor immune dysfunction and exclusion (TIDE) were utilized to access the tumor immune landscape of LGG samples. The results demonstrated that the immune landscapes of different risk stratifications differed significantly. Furthermore, we explored the association between the CRL risk signature and immunotherapy effectiveness using the IMvigor210 dataset. Several prospective drugs targeting samples with high scores were predicted, namely, MG-132, PLX-4720, AZD6482, and BMS-536924. We verified the antiglioma effect of MG-132 in vitro. Moreover, experiments conducted in vitro demonstrated that knockdown of the expression of the CRLs TPRG1-AS1 and LYRM4-AS1 might impair the migration and proliferation capacity of glioma cells. Taken together, these results indicate that CRLs are linked to prognosis and immune characteristics in LGG and give innovative therapeutic methods for individuals with LGG across different risk stratifications.

cuproptosis; immune infiltration; immune microenvironment; lncRNA; primary lower-grade glioma.