Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells

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...

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Autores principales:	Haiyang Zhang, Meng Wang, Yi He, Ting Deng, Rui Liu, Weixue Wang, Kegan Zhu, Ming Bai, Tao Ning, Haiou Yang, Ying Liu, Junyi Wang, Yi Ba
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/2292fee0bc654f778ef0e718cb0897d5
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spelling	oai:doaj.org-article:2292fee0bc654f778ef0e718cb0897d52021-12-05T12:04:24ZChemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells10.1038/s41419-021-04406-z2041-4889https://doaj.org/article/2292fee0bc654f778ef0e718cb0897d52021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04406-zhttps://doaj.org/toc/2041-4889Abstract 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.Haiyang ZhangMeng WangYi HeTing DengRui LiuWeixue WangKegan ZhuMing BaiTao NingHaiou YangYing LiuJunyi WangYi BaNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 12, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Haiyang Zhang Meng Wang Yi He Ting Deng Rui Liu Weixue Wang Kegan Zhu Ming Bai Tao Ning Haiou Yang Ying Liu Junyi Wang Yi Ba Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells
description	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.
format	article
author	Haiyang Zhang Meng Wang Yi He Ting Deng Rui Liu Weixue Wang Kegan Zhu Ming Bai Tao Ning Haiou Yang Ying Liu Junyi Wang Yi Ba
author_facet	Haiyang Zhang Meng Wang Yi He Ting Deng Rui Liu Weixue Wang Kegan Zhu Ming Bai Tao Ning Haiou Yang Ying Liu Junyi Wang Yi Ba
author_sort	Haiyang Zhang
title	Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells
title_short	Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells
title_full	Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells
title_fullStr	Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells
title_full_unstemmed	Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells
title_sort	chemotoxicity-induced exosomal lncfero regulates ferroptosis and stemness in gastric cancer stem cells
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/2292fee0bc654f778ef0e718cb0897d5
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Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells

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