CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer
CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer
复制标题
CAF 分泌的 miR-522 抑制铁死亡并促进胃癌的获得性化疗耐药。
DOI：
10.1186/s12943-020-01168-8
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发表时间：
2020-02-27
期刊：
影响因子：
37.3
通讯作者：
Ba, Yi
中科院分区：
文献类型：
--
作者：
Zhang, Haiyang;Deng, Ting;Ba, Yi
背景铁凋亡（Ferroptosis）是一种新型的非凋亡性细胞死亡模式，由毒性脂质过氧化物（lipid-ROS）以铁依赖的方式诱导。癌症相关成纤维细胞（CAF）通过分泌各种生物活性物质（包括外泌体）支持肿瘤进展和耐药性。然而，CAFs在调节脂质代谢以及癌细胞的铁凋亡中的作用仍然是未被探索的，仍然是migmart. MethodsFerroptosis相关基因在胃癌（GC）中的筛选通过质谱; exosomes通过超速离心分离和CAF分泌的miRNAs通过RT-qPCR测定。Erastin被用来诱导ferroptosis，和ferroptosis水平进行了评估，通过测量脂质-ROS，细胞活力和线粒体膜potential.ResultsHere，我们提供的临床证据表明，花生四烯酸脂氧合酶15（ALOX 15）是密切相关的脂质-ROS生产在胃癌，和外泌体-miR-522作为一个潜在的抑制剂ALOX 15。通过使用原代基质细胞和癌细胞，我们证明exosome-miR-522主要来源于肿瘤微环境中的CAFs。此外，发现异质核核糖核蛋白A1（hnRNPA 1）介导miR-522包装到外泌体中，并且泛素特异性蛋白酶7（USP 7）通过去泛素化稳定hnRNPA 1。重要的是，顺铂和紫杉醇通过激活USP 7/hnRNPA 1轴促进CAFs分泌miR-522，导致ALOX 15抑制和癌细胞内脂质-ROS积累减少，最终导致化疗敏感性降低。由USP 7、hnRNPA 1、exo-miR-522和ALOX 15组成的细胞间通路揭示了GC获得性化疗耐药的新机制。
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