CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer

Haiyang Zhang,Hailong Wang,Ming Bai,Zhi Ji,Yi Ba,Tao Ning,Rui Liu,Dongying Liu,Haiou Yang,Ting Deng,Qiumo Zhang,Le Zhang,Hongli Li,Xinyi Wang,Guoguang Ying,Shaohua Ge,Dan Lin,Yuchong Yang

doi:10.1186/s12943-020-01168-8

Abstract

BackgroundFerroptosis 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.MethodsFerroptosis-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.ResultsHere, 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.ConclusionsThe 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

Highlights

Cell death is strictly regulated by complex intracellular and extracellular signals, and is essential for various biological processes, including homeostasis, development and disease
Screening of the key genes related to ferroptosis in gastric cancer (GC) Previous studies have shown that 15-lipoxygenase (ALOX15) plays a key role in mediating the production of Lipid ROS in various types of tissues and tumors [28,29,30]
arachidonate lipoxygenase 15 (ALOX15), one of the key genes leading to ferroptosis, showed a sharp decrease, while the levels of ubiquitin-specific protease 7 (USP7) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) were clearly increased in tumor tissues (Fig. 1a)

Summary

Introduction

Cell death is strictly regulated by complex intracellular and extracellular signals, and is essential for various biological processes, including homeostasis, development and disease. Cancer-associated fibroblasts (CAFs) are the main type of stromal cells in tumor microenvironment and exhibit distinct tumorigenic properties [9,10,11]. Recent studies indicated that exosomes derived from CAFs promote tumor metastasis and increase chemoresistance of cancer cells [17, 18]. The potential roles of exosomes derived from CAFs in regulating lipid metabolism and ferroptosis in cancer cells have not been defined yet. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. The role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic

Methods

Results

Discussion

Conclusion