LncRNAs Target Ferroptosis-Related Genes and Impair Activation of CD4+ T Cell in Gastric Cancer

Abstract

Gastric cancer (GC) is a malignant disease of the digestive tract and a life-threatening disease worldwide. Ferroptosis, an iron-dependent cell death caused by lipid peroxidation, is reported to be highly correlated with gastric tumorigenesis and immune cell activity. However, the underlying relationship between ferroptosis and the tumor microenvironment in GC and potential intervention strategies have not been unveiled. In this study, we profiled the transcriptome and prognosis data of ferroptosis-related genes (FRGs) in GC samples of the TCGA-STAD dataset. The infiltrating immune cells in GC were estimated using the CIBERSORT and XCELL algorithms. We found that the high expression of the hub FRGs (MYB, PSAT1, TP53, and LONP1) was positively correlated with poor overall survival in GC patients. The results were validated in an external GC cohort (GSE62254). Further immune cell infiltration analysis revealed that CD4+ T cells were the major infiltrated cells in the tumor microenvironment of GC. Moreover, the hub FRGs were significantly positively correlated with activated CD4+ T cell infiltration, especially Th cells. The gene features in the high-FRG score group were enriched in cell division, DNA repair, protein folding, T cell receptor, Wnt and NIK/NF-kappaB signaling pathways, indicating that the hub FRGs may mediate CD4+ T cell activation by these pathways. In addition, an upstream transcriptional regulation network of the hub FRGs by lncRNAs was also developed. Three lncRNAs (A2M-AS1, C2orf27A, and ZNF667-AS1) were identified to be related to the expression of the hub FRGs. Collectively, these results showed that lncRNA A2M-AS1, C2orf27A, and ZNF667-AS1 may target the hub FRGs and impair CD4+ T cell activation, which finally leads to poor prognosis of GC. Effective interventions for the above lncRNAs and the hub FRGs can help promote CD4+ T cell activation in GC patients and improve the efficacy of immunotherapy. These findings provide a novel idea of GC immunotherapy and hold promise for future clinical application.

Are Antisense Long Non-Coding RNA Related to COVID-19?

“…The lncRNA A2M antisense RNA1 (A2M-AS1) is a novel lncRNA identified as one of the upstream regulators that might affect the expression of ferroptosis-related genes [ 18 ].…”

“…The ability to avoid infection depends on the adaptive immune system, and during the first critical hours and days of exposure to a new pathogen, we rely upon our innate immune system. Ferroptosis, a distinct form of programmed cell death driven by iron, is involved in regulating CD4+ T cell homeostasis, which enhances the function of follicular helper T cells during infection and following vaccination [ 18 ].…”

Lipid Metabolic-Related Signature CYP19A1 is a Potential Biomarker for Prognosis and Immune Cell Infiltration in Gastric Cancer

“…It was reported that MYB and SERPINE1 are directly or indirectly associate with gastric cancer cell proliferation and metastasis. 38,39 MTTP is an ER resident protein and its variant is linked to human diseases. 40 However, the functions of CYP19A1 in tumor progression have not been reported in gastric cancer.…”

Pyroptosis-related gene-based prognostic signature for predicting the overall survival of oral squamous cell carcinoma patients

“…XCELL in TIMER (http://timer.comp-genomics.org/) was used to evaluate the percentage of immune cell types, that is, the infiltration levels of diverse types of immune cells among OSCC samples as previously described (26). Further, the differences in immune cell invasion between two risk groups was assessed using SSGESA according to the previous studies (27).…”