Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis
Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis
复制标题
外泌体miR-4443通过调节FSP1 m6A修饰介导的铁凋亡促进非小细胞肺癌的顺铂耐药
DOI：
10.1016/j.lfs.2021.119399
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发表时间：
2021-04-01
期刊：
影响因子：
6.1
通讯作者：
Cang, Shundong
中科院分区：
文献类型：
--
作者：
Song, Zhiyu;Jia, Gang;Cang, Shundong
目的：miRNA 的外泌体转移影响受体细胞增殖和化疗耐药性。在此，我们的目的是研究外泌体miRNA在控制非小细胞肺癌（NSCLC）顺铂耐药中的作用。主要方法：从对顺铂治疗低反应或高反应的NSCLC患者中收集配对的肿瘤和正常组织来源的外泌体。结果显示，与顺铂敏感的组织来源的外泌体相比，顺铂耐药的 NSCLC 肿瘤组织来源的外泌体中 microRNA-4443 (miR-4443) 水平上调。顺铂耐药细胞（A549-R）是从亲本细胞（A549-S）产生的。耐药外泌体通过将 miR-4443 转移至敏感细胞而赋予顺铂耐药性。此外，miR-4443 的过表达在体外抑制顺铂治疗诱导的 FSP1 介导的铁死亡，并增强体内肿瘤生长。 主要发现：通过生物信息学分析和荧光素酶测定，确认 METTL3 是 miR-4443 的直接靶基因。进一步的机制分析表明，miR-4443 通过 METLL3 以 m6A 方式调节 FSP1 的表达。意义：我们的研究结果为 NSCLC 的化疗耐药性提供了更深入的了解，并支持靶向铁死亡的治疗潜力。
Aims: Exosomal transfer of miRNAs affects recipient cell proliferation and chemoresistance. Here, we aimed to investigate the role of exosomal miRNAs in controlling cisplatin resistance in non-small cell lung carcinoma (NSCLC).Main methods: Paired tumor and normal tissue-derived exosomes were collected from NSCLC patients with low or high responsiveness to cisplatin treatment. The results showed that the microRNA-4443 (miR-4443) level was upregulated in cisplatin-resistant NSCLC tumor tissue-derived exosomes compared with cisplatin-sensitive tissuederived exosomes. Cisplatin-resistant cells (A549-R) were generated from the parental cells (A549-S). Resistant exosomes conferred cisplatin resistance by transferring miR-4443 to sensitive cells. Moreover, overexpression of miR-4443 inhibited FSP1-mediated ferroptosis induced by cisplatin treatment in vitro and enhanced tumor growth in vivo.Key findings: Through bioinformatics analysis and luciferase assays, METTL3 was confirmed as a direct target gene of miR-4443. Further mechanistic analysis showed that miR-4443 regulated the expression of FSP1 in an m6A manner via METLL3.Significance: Our findings provide more in-depth insight into the chemoresistance of NSCLC and support the therapeutic potential of targeting ferroptosis.