Abstract
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.
Highlights
Solid tumors, including gastric cancer (GC), usually exhibit intratumoral in cell types, cellular composition, intercellular cytokines, matrix proteins, metabolites, and vesicles [1,2,3]
The results showed that both mRNA and protein levels were significantly increased in gastric cancer stem cells (GCSCs) compared with GC cells (Fig. 3C, SCD1 is closely related to lipid metabolism and ferroptosis in D)
It was GCSCs shown that SCD1 protein was upregulated more than threefold To test the function of lncFERO derived from GC cells in the (Fig. 1B, C), but SCD1 mRNA only showed slight increase in tumor regulation of ferroptosis in GCSCs, GC exosomes were isolated and tissues (Fig. 1D)
Summary
Solid tumors, including gastric cancer (GC), usually exhibit intratumoral in cell types, cellular composition, intercellular cytokines, matrix proteins, metabolites, and vesicles [1,2,3]. Exosomal lnc-ENDOG-1:1 was found to be linked correlated with SCD1 expression (Fig. 2G), but negatively linked with lipid ROS production on the dynamic regulation of ferroptosis with lipid ROS production (Fig. 2H). These results suggested that in GCSCs, and was named exosomal lncFERO (exo-lncFERO). Our study illustrated a novel pathway compris- metastasis [44], CSCs have been identified in GC [45, 46] In this ing exosomes, lncRNA, hnRNPA1, and SCD1 between GC and CSC, study, CSCs were obtained from GC cell lines by using FBS-free and suggested that targeting ferroptosis-related genes in CSC medium and nonadherent plates. We detected the expression of stemness-associated genes, including NOTCH1, SOX9, and OCT4
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