C-myc对Erastin诱导肝癌细胞铁死亡的影响

Effect of C-myc on Erastin-induced ferroptosis and its mechanism in hepatoma carcinoma cell

目的通过生物信息学筛选肝癌细胞铁死亡潜在药物靶点,并实验验证和检测靶点抑制剂与铁死亡诱导剂Erastin联合用药的效果。方法利用高通量基因表达数据库(GEO)数据(GSE104462)进行基因富集分析,探索肝癌细胞中Erastin诱导的铁死亡相关通路。在肝癌细胞系SK-Hep-1中利用验证性CCK-8、细胞凋亡以及划痕实验探究C-myc及其抑制剂10074-G5对肝癌SK-Hep-1细胞铁死亡的影响。结果基因富集分析发现,相比于对照组,Erastin诱导铁死亡时肝癌细胞中C-myc信号通路基因显著下调性富集;验证性CCK-8实验表明,C-myc过表达可减弱肝癌SK-Hep-1细胞对Erastin诱导铁死亡的敏感性,而10074-G5增强其敏感性;细胞凋亡、划痕实验表明,联用抑制剂10074-G5可增强Erastin对肝癌细胞的杀伤和迁移抑制作用;且C-myc过表达可部分消除Erastin诱导升高的二价铁离子,抑制剂10074-G5可增强Erastin诱导升高的二价铁离子。结论C-myc信号对肝癌细胞铁死亡起抑制性作用,联用C-myc抑制剂可显著增强诱导肝癌细胞铁死亡的敏感性。

Objective To investigate the cellular target for inhibiting Erastin-induced ferroptosisin HCC cells via bioinformatics and experiments.Methods Gene enrichment analysis was conducted to screen out Erastin-induced ferroptosisrelated signaling pathways based on GSE104462.Cell viability,apoptosis and scratch assays were used to validate the effect of C-myc and its inhibitor 10074-G5 on ferroptosis in SK-Hep-1 cells.Results Gene enrichment analysis revealed that the C-myc related signaling pathway was enriched in the Erastin group compared with the control group.Cell viability assays showed that C-myc overexpression reduced the sensibility of SK-Hep-1 cells to Erastin-induced ferroptosis while10074-G5 increased the sensibility.Apoptosis and scratch assays showed that 10074-G5 enhanced the killing effect and migration inhibition of Erastin on SK-Hep-1 cells.In addition,C-myc overexpression partially eliminated Erastininduced Fe2+while 10074-G5 elevated Erastin-induced Fe2+.Conclusion C-myc can mitigate Erastin-induced ferroptosis,while C-myc inhibitor 10074-G5 can enhanced Erastin-induced ferroptosis in HCC cells.