CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer
Abstract Background Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including ex...
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2020-02-01
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Series: | Molecular Cancer |
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Online Access: | http://link.springer.com/article/10.1186/s12943-020-01168-8 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Haiyang Zhang Ting Deng Rui Liu Tao Ning Haiou Yang Dongying Liu Qiumo Zhang Dan Lin Shaohua Ge Ming Bai Xinyi Wang Le Zhang Hongli Li Yuchong Yang Zhi Ji Hailong Wang Guoguang Ying Yi Ba |
spellingShingle |
Haiyang Zhang Ting Deng Rui Liu Tao Ning Haiou Yang Dongying Liu Qiumo Zhang Dan Lin Shaohua Ge Ming Bai Xinyi Wang Le Zhang Hongli Li Yuchong Yang Zhi Ji Hailong Wang Guoguang Ying Yi Ba CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer Molecular Cancer Ferroptosis Cancer-associated fibroblasts Exosomes miR-522 GC |
author_facet |
Haiyang Zhang Ting Deng Rui Liu Tao Ning Haiou Yang Dongying Liu Qiumo Zhang Dan Lin Shaohua Ge Ming Bai Xinyi Wang Le Zhang Hongli Li Yuchong Yang Zhi Ji Hailong Wang Guoguang Ying Yi Ba |
author_sort |
Haiyang Zhang |
title |
CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer |
title_short |
CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer |
title_full |
CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer |
title_fullStr |
CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer |
title_full_unstemmed |
CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer |
title_sort |
caf secreted mir-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer |
publisher |
BMC |
series |
Molecular Cancer |
issn |
1476-4598 |
publishDate |
2020-02-01 |
description |
Abstract Background Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic. Methods Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential. Results Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity. Conclusions The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC. Graphical abstract |
topic |
Ferroptosis Cancer-associated fibroblasts Exosomes miR-522 GC |
url |
http://link.springer.com/article/10.1186/s12943-020-01168-8 |
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doaj-0f7fec71076041c089b993d3f09403782020-11-25T04:04:45ZengBMCMolecular Cancer1476-45982020-02-0119111710.1186/s12943-020-01168-8CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancerHaiyang Zhang0Ting Deng1Rui Liu2Tao Ning3Haiou Yang4Dongying Liu5Qiumo Zhang6Dan Lin7Shaohua Ge8Ming Bai9Xinyi Wang10Le Zhang11Hongli Li12Yuchong Yang13Zhi Ji14Hailong Wang15Guoguang Ying16Yi Ba17Tianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyTianjin 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 TherapyAbstract Background Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic. Methods Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential. Results Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity. Conclusions The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC. Graphical abstracthttp://link.springer.com/article/10.1186/s12943-020-01168-8FerroptosisCancer-associated fibroblastsExosomesmiR-522GC |