Silencing LCN2 enhances RSL3-induced ferroptosis in T cell acute lymphoblastic leukemia

Chuan Tian; Min Zheng; Xiang Lan; Lili Liu; Zhonglv Ye; Chengyan Li

doi:10.1016/j.gene.2023.147597

Silencing LCN2 enhances RSL3-induced ferroptosis in T cell acute lymphoblastic leukemia

Gene. 2023 Aug 30:879:147597. doi: 10.1016/j.gene.2023.147597. Epub 2023 Jun 28.

Authors

Chuan Tian¹, Min Zheng², Xiang Lan¹, Lili Liu¹, Zhonglv Ye¹, Chengyan Li³

Affiliations

¹ Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, No. 57, South Renmin Avenue, Zhanjiang City, Guangdong Province 524001, China.
² Department of Obstetrics, Affiliated Hospital of Guangdong Medical University, No. 57, South Renmin Avenue, Zhanjiang City, Guangdong Province 524001, China.
³ Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, No. 57, South Renmin Avenue, Zhanjiang City, Guangdong Province 524001, China. Electronic address: lichengyan@gdmu.edu.cn.

PMID: 37390872
DOI: 10.1016/j.gene.2023.147597

Abstract

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.

Keywords: Ferroptosis; Hub gene; Lipocalin 2; Protein-protein interaction network; T cell acute lymphoblastic leukemia.

MeSH terms

Ferroptosis* / genetics
Humans
Iron
Lipocalin-2 / genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / genetics
T-Lymphocytes

Substances

Lipocalin-2
Iron
LCN2 protein, human