Yao Fuwen, Zhan Yongqiang, Pu Zuhui, Lu Ying, Chen Jiao, Deng Jing, Wu Zijing, Chen Binhua, Chen Jinjun, Tian Kuifeng, Ni Yong, Mou Lisha
Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.
Front Cell Dev Biol. 2021 Dec 13;9:797339. doi: 10.3389/fcell.2021.797339. eCollection 2021.
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 (, , , and ) 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 (, , and ) were identified to be related to the expression of the hub FRGs. Collectively, these results showed that lncRNA , , and 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.
胃癌（GC）是一种消化道恶性疾病，在全球范围内都是一种危及生命的疾病。铁死亡是一种由脂质过氧化引起的铁依赖性细胞死亡，据报道与胃肿瘤发生和免疫细胞活性高度相关。然而，铁死亡与GC肿瘤微环境之间的潜在关系以及潜在的干预策略尚未明确。在本研究中，我们分析了TCGA-STAD数据集中GC样本中铁死亡相关基因（FRGs）的转录组和预后数据。使用CIBERSORT和XCELL算法估计GC中浸润的免疫细胞。我们发现核心FRGs（ 、 、 和 ）的高表达与GC患者较差的总生存期呈正相关。结果在外部GC队列（GSE62254）中得到验证。进一步的免疫细胞浸润分析表明，CD4 T细胞是GC肿瘤微环境中主要的浸润细胞。此外，核心FRGs与活化的CD4 T细胞浸润，尤其是Th细胞显著正相关。高FRG评分组的基因特征在细胞分裂、DNA修复、蛋白质折叠、T细胞受体、Wnt和NIK/NF-κB信号通路中富集，表明核心FRGs可能通过这些通路介导CD4 T细胞活化。此外，还构建了lncRNAs对核心FRGs的上游转录调控网络。鉴定出三种lncRNAs（ 、 和 ）与核心FRGs的表达相关。总体而言，这些结果表明lncRNA 、 和 可能靶向核心FRGs并损害CD4 T细胞活化，最终导致GC预后不良。针对上述lncRNAs和核心FRGs的有效干预措施有助于促进GC患者的CD4 T细胞活化并提高免疫治疗效果。这些发现为GC免疫治疗提供了新思路，具有未来临床应用的前景。
