Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
Cell Death Dis. 2021 Nov 29;12(12):1116. doi: 10.1038/s41419-021-04406-z.
Cancer stem cells (CSCs) are an important cause of tumor recurrence and drug resistance. As a new type of cell death that relies on iron ions and is strictly regulated by intracellular and extracellular signals, the role of ferroptosis in tumor stem cells deserves extensive attention. Mass spectrum was applied to screen for ferroptosis-related proteins in gastric cancer (GC). Sphere-formation assay was used to estimate the stemness of gastric cancer stem cells (GCSCs). Exosomal lnc-ENDOG-1:1 (lncFERO) was isolated by ultracentrifugation. Ferroptosis was induced by erastin and was assessed by detecting lipid ROS, mitochondrial membrane potential, and cell death. Furthermore, a series of functional in vitro and in vivo experiments were conducted to evaluate the effects of lncFERO on regulating ferroptosis and chemosensitivity in GCSCs. Here, we showed that stearoyl-CoA-desaturase (SCD1) played a key role in regulating lipid metabolism and ferroptosis in GCSCs. Importantly, exosomal lncFERO (exo-lncFERO) derived from GC cells was demonstrated to promote SCD1 expression by directly interacting with SCD1 mRNA and recruiting heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which resulted in the dysregulation of PUFA levels and the suppression of ferroptosis in GCSCs. Moreover, we found that hnRNPA1 was also involved in lncFERO packing into exosomes in GC cells, and both in vitro and in vivo data suggested that chemotoxicity induced lncFERO secretion from GC cells by upregulating hnRNPA1 expression, leading to enhanced stemness and acquired chemo-resistance. All these data suggest that GC cells derived exo-lncFERO controls GCSC tumorigenic properties through suppressing ferroptosis, and targeting exo-lncFERO/hnRNPA1/SCD1 axis combined with chemotherapy could be a promising CSC-based strategy for the treatment of GC.
癌症干细胞（CSC）是肿瘤复发和耐药的重要原因。铁依赖性细胞死亡作为一种新型的细胞死亡方式，严格受细胞内和细胞外信号的调控，其在肿瘤干细胞中的作用值得广泛关注。采用质谱法筛选胃癌（GC）中的铁死亡相关蛋白。球体形成实验用于评估胃癌干细胞（GCSC）的干性。超速离心分离外泌体 lnc-ENDOG-1：1（lncFERO）。用 erastin 诱导铁死亡，并通过检测脂质 ROS、线粒体膜电位和细胞死亡来评估。此外，还进行了一系列体外和体内功能实验，以评估 lncFERO 对调节 GCSC 中铁死亡和化疗敏感性的影响。在这里，我们表明硬脂酰辅酶 A 去饱和酶（SCD1）在 GCSC 中调节脂质代谢和铁死亡中起着关键作用。重要的是，来自 GC 细胞的外泌体 lncFERO（exo-lncFERO）被证明通过直接与 SCD1 mRNA 相互作用并募集异质核核糖核蛋白 A1（hnRNPA1）来促进 SCD1 表达，导致多不饱和脂肪酸（PUFA）水平失调，并抑制 GCSC 中的铁死亡。此外，我们发现 hnRNPA1 也参与了 GC 细胞中 lncFERO 的包装进入外泌体，并且体外和体内数据表明，通过上调 hnRNPA1 表达，化疗毒性诱导 GC 细胞分泌 lncFERO，导致增强的干性和获得的化疗耐药性。所有这些数据表明，GC 细胞衍生的 exo-lncFERO 通过抑制铁死亡来控制 GCSC 的肿瘤发生特性，靶向 exo-lncFERO/hnRNPA1/SCD1 轴联合化疗可能是一种有前途的基于 CSC 的 GC 治疗策略。
