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

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...

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Autores principales: Zhang, Haiyang, Wang, Meng, He, Yi, Deng, Ting, Liu, Rui, Wang, Weixue, Zhu, Kegan, Bai, Ming, Ning, Tao, Yang, Haiou, Liu, Ying, Wang, Junyi, Ba, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629982/
https://www.ncbi.nlm.nih.gov/pubmed/34845198
http://dx.doi.org/10.1038/s41419-021-04406-z
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author Zhang, Haiyang
Wang, Meng
He, Yi
Deng, Ting
Liu, Rui
Wang, Weixue
Zhu, Kegan
Bai, Ming
Ning, Tao
Yang, Haiou
Liu, Ying
Wang, Junyi
Ba, Yi
author_facet Zhang, Haiyang
Wang, Meng
He, Yi
Deng, Ting
Liu, Rui
Wang, Weixue
Zhu, Kegan
Bai, Ming
Ning, Tao
Yang, Haiou
Liu, Ying
Wang, Junyi
Ba, Yi
author_sort Zhang, Haiyang
collection PubMed
description 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.
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spelling pubmed-86299822021-12-01 Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells Zhang, Haiyang Wang, Meng He, Yi Deng, Ting Liu, Rui Wang, Weixue Zhu, Kegan Bai, Ming Ning, Tao Yang, Haiou Liu, Ying Wang, Junyi Ba, Yi Cell Death Dis Article 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. Nature Publishing Group UK 2021-11-29 /pmc/articles/PMC8629982/ /pubmed/34845198 http://dx.doi.org/10.1038/s41419-021-04406-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Haiyang
Wang, Meng
He, Yi
Deng, Ting
Liu, Rui
Wang, Weixue
Zhu, Kegan
Bai, Ming
Ning, Tao
Yang, Haiou
Liu, Ying
Wang, Junyi
Ba, Yi
Chemotoxicity-induced exosomal lncFERO regulates ferroptosis and stemness in gastric cancer stem cells
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629982/
https://www.ncbi.nlm.nih.gov/pubmed/34845198
http://dx.doi.org/10.1038/s41419-021-04406-z
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