沉默 LCN2 增强 RSL3 诱导的 T 细胞急性淋巴细胞白血病中的铁死亡。
Silencing LCN2 enhances RSL3-induced ferroptosis in T cell acute lymphoblastic leukemia.
机构信息
Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, No. 57, South Renmin Avenue, Zhanjiang City, Guangdong Province 524001, China.
Department of Obstetrics, Affiliated Hospital of Guangdong Medical University, No. 57, South Renmin Avenue, Zhanjiang City, Guangdong Province 524001, China.
出版信息
Gene. 2023 Aug 30;879:147597. doi: 10.1016/j.gene.2023.147597. Epub 2023 Jun 28.
BACKGROUND
T-cell acute lymphoblastic leukemia (T-ALL) is a life-threatening malignancy and therapeutic toxicity remains a huge challenge for survival rates. A novel iron-dependent form of cell death, ferroptosis, shows potentials in cancer therapy. This study aimed to identify ferroptosis-associated hub genes within a proteinprotein interaction (PPI) network.
METHODS
We screened differential expressed genes (DEGs) in GSE46170 dataset and obtained ferroptosis-related genes from FerrDb database. Through overlapping between DEGs and ferroptosis-related genes, ferroptosis-associated DEGs were identified for further PPI network construction. Molecular complex detection (MCODE) algorithm in Cytoscape was employed to determine tightly connected protein clusters. Chord diagram of Gene Ontology (GO) was generated to reveal the potential biological process of hub genes. Through transfection with siRNA of lipocalin 2 (LCN2) into TALL cells, the regulatory role of LCN2 in ferroptosis was investigated.
RESULTS
Venn diagram identified a total of 37 ferroptosis-associated DEGs between GSE46170 and ferroptosis-associated genes, which were mainly enriched in ferroptosis and necroptosis. Based on PPI network analysis, 5 hub genes (LCN2, LTF, HP, SLC40A1 and TFRC) were found. These hub genes were involved in iron ion transport and could distinguish T-ALL from normal individuals. Further experimental studies demonstrated that LCN2 was highly expressed in T-ALL, while silencing LCN2 promoted RSL3-induced ferroptotic cell death in T-ALL cells.
CONCLUSION
This study identified novel ferroptosis-associated hub genes, which shed new insights into the underlying mechanism of ferroptosis in T-ALL and also provide promising therapeutic targets for T-ALL.
背景
T 细胞急性淋巴细胞白血病（T-ALL）是一种危及生命的恶性肿瘤，治疗毒性仍然是提高生存率的巨大挑战。一种新型的铁依赖性细胞死亡形式，铁死亡，在癌症治疗中显示出潜力。本研究旨在鉴定蛋白质-蛋白质相互作用（PPI）网络中的铁死亡相关枢纽基因。
方法
我们从 GSE46170 数据集筛选差异表达基因（DEGs），并从 FerrDb 数据库获得铁死亡相关基因。通过 DEGs 和铁死亡相关基因之间的重叠，鉴定出铁死亡相关 DEGs 以进一步构建 PPI 网络。Cytoscape 中的分子复合物检测（MCODE）算法用于确定紧密连接的蛋白质簇。生成基因本体论（GO）的和弦图以揭示枢纽基因的潜在生物学过程。通过向 TALL 细胞转染载脂蛋白 2（LCN2）的 siRNA，研究了 LCN2 在铁死亡中的调节作用。
结果
Venn 图确定了 GSE46170 和铁死亡相关基因之间总共 37 个铁死亡相关 DEGs，这些基因主要富集在铁死亡和坏死性凋亡中。基于 PPI 网络分析，发现了 5 个枢纽基因（LCN2、LTF、HP、SLC40A1 和 TFRC）。这些枢纽基因参与铁离子转运，可以区分 T-ALL 与正常个体。进一步的实验研究表明，LCN2 在 T-ALL 中高表达，而沉默 LCN2 可促进 RSL3 诱导的 T-ALL 细胞铁死亡。
结论
本研究鉴定了新的铁死亡相关枢纽基因，为 T-ALL 中铁死亡的潜在机制提供了新的见解，并为 T-ALL 提供了有前途的治疗靶点。
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