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.
Highlights
Gastric cancer, as the third leading cause of cancer-related deaths, is responsible for a high burden of disease globally (Sung et al, 2021)
To identify the key genes involved in the process of gastric carcinogenesis as well as prognosis, we conducted an in-depth analysis of public RNA-Seq data from the The Cancer Genome Atlas (TCGA)-STAD dataset of 375 gastric cancer (GC) and 32 adjacent normal tissues
Three long noncoding RNAs (lncRNAs) with the strongest regulatory relationship with the hub ferroptosis-related genes (FRGs) were A2MAS1, C2orf27A, and ZNF667-AS1 (Figure 6E). Since they were negatively correlated with activated CD4+ T cell infiltration (Supplementary Figure S3), we demonstrated that the three lncRNAs might potentially negatively regulate the hub FRGs, which in turn inhibit the activation of CD4+ T cells
Summary
As the third leading cause of cancer-related deaths, is responsible for a high burden of disease globally (Sung et al, 2021). In GC, ferroptosis is reported to be related to tumor cell proliferation and cancer therapeutic efficacy (Zhang et al, 2020; Ma et al, 2021). Recent studies have shown the relationship between ferroptosis and the immune microenvironment in the tumorigenesis and prognosis of GC (Zhang et al, 2020). Treg cells are defined as T cells in charge of suppression of potentially deleterious activities of Th cells, regulation of the effector class of the immune response, and suppression of T-cell activation (Corthay, 2009; Arumugam and Sugin Lal Jabaris, 2021). The study of CD4+ T cells has tremendous potential to contribute to cancer immunotherapy (Yuan et al, 2017). The function of ferroptosis in the regulation of the GC microenvironment and the upstream regulators of ferroptosisrelated genes (FRGs) are worth further exploration
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