Identification and validation of ferroptosis-related lncRNA signatures as a novel prognostic model for glioma

Abstract

Background: Ferroptosis is a newly discovered form of regulated cell death with distinct properties and recognizing functions involved in physical conditions or various diseases, including cancers. However, the relationship between gliomas and ferroptosis-related lncRNAs (FRLs) remains unclear.Methods: We collected a total of 1850 samples from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEX) databases, including 698 tumor and 1,152 normal samples. A list of ferroptosis-related genes was downloaded from the Ferrdb website. Differentially expressed FRLs (DEFRLS) were analyzed using the “limma” package in R software. Subsequently, prognosis-related FRLs were obtained by univariate Cox analysis. Finally, a prognostic model based on the 3 FRLs was constructed using Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm. The prognostic power of the model was assessed using receiver operating characteristic (ROC) curve analysis and Kaplan-Meier (K-M) survival curve analysis. In addition, we further explored the relationship of the immune landscape and somatic mutations to prognostic model characteristics. Finally, we validated the function of LINC01426 in vitro.Results: We successfully constructed a 3-FRLs signature and classified glioma patients into high-risk and low-risk groups based on the risk score calculated from this signature. Compared with traditional clinicopathological features [age, sex, grade, isocitrate dehydrogenase (IDH) status], the prognostic accuracy of this model is more stable and stronger. Additionally, the model had stable predictive power for overall survival over a 5-year period. In addition, we found significant differences between the two groups in cellular immunity, the numbers of many immune cells, including NK cells, CD4+, CD8+ T-cells, and macrophages, and the expression of many immune-related genes. Finally, the two groups were also significantly different at the level of somatic mutations, especially in glioma prognosis-related genes such as IDH1 and ATRX, with lower mutation rates in the high-risk group leading to poorer prognosis. Finally, we found that the ferroptosis process of glioma cells was inhibited after knocking down the expression of LINC01426.Conclusion: The proposed 3-FRL signature is a promising biomarker for predicting prognostic features in glioma patients.

Identification and validation of a ferroptosis-related lncRNA signature to robustly predict the prognosis, immune microenvironment, and immunotherapy efficiency in patients with clear cell renal cell carcinoma

“…LINC00894 enhances cell proliferation and invasion by binding with miR-429 to mediate ZEB1 expression in breast cancer ( Meng, Shao & Feng, 2021 ); what’s more, in thyroid cancer, its increased expression reduces the oncogenic properties by sponging let-7e−5p to promote TIA-1 expression ( Chen et al, 2022a ). LINC01426 modulates CTBP1/miR-423-5p/FOXM1 axis via interacting with IGF2BP1 to aggravate ccRCC progression ( Jiang et al, 2021b ), it also aggravates the malignant progression through miR-661/Mdm2 axis in glioma ( Shu et al, 2022 ), it serves as a prognostic indicator in lung adenocarcinoma by triggering growth and metastasis ( Deng et al, 2022 ), what’s more, in a recently reported study on ferroptosis-related lncRNAs of glioma, LINC01426 was identified to be related to ferroptosis, its knockdown could significantly increase in the Fe 2+ levels and the erastin-induced ROS levels in glioma cells ( Huang et al, 2022 ). LncRNA DUXAP8 acts as an oncogene in most tumors, its abnormal overexpression is associated with the proliferation, invasion, migration, anti-autophagy, and poor prognosis of tumors ( Wang et al, 2022a ; Wang et al, 2022b ), it may act as a potential therapeutic target for cancer ( Wang et al, 2022b ); in a research on identification of necroptosis-related lncRNAs in hepatocellular carcinoma, DUXAP8 was identified as a prognostic lncRNA and related to patients’ prognosis ( Chen et al, 2022b ); In addition to our research, other studies have also found that it is involved in the process of ferroptosis in tumor, such as: it can act with ferroptosis-associated gene FANCD2 to form DUXAP8-miR-29c-FANCD2 axe in hepatocellular carcinoma ( Yang et al, 2022 ), it was also identified as one of ferroptosis-related lncRNAs in kidney carcinoma ( Xing et al, 2021 ).…”