TP53 mitigates cisplatin resistance in non-small cell lung cancer by mediating the effects of resistant cell-derived exosome mir-424-5p

作者：Yan Deng, Hao Ding, Yanhua Zhang, Xudong Feng, Qing Ye, Rui Tian, Yuchuan Xu, Qingqing He, Qiaofen Fu, Rongqing Li · 发表于：Heliyon · 年份：2024 · DOI：10.1016/j.heliyon.2024.e26853 · 被引用次数：4 · 研究领域：Extracellular vesicles in disease、MicroRNA in disease regulation、Silymarin and Mushroom Poisoning

Background: Cisplatin (DDP) is the principal agent used for chemotherapy in patients with non-small cell lung cancer (NSCLC). Nevertheless, DDP resistance is an essential cause for a worse prognosis of patient. Therefore, this study proposes to discover features of miR-424-5p in DDP resistance of NSCLC. Method: . TargetScan and JASPAR databases predicted the potential molecular mechanism of miR-424-5p. A549-and A549/DDP-derived exosomes were isolated and characterized using a transmission electron microscope and nanoparticle tracking analysis. Result: Overexpression of miR-424-5p facilitated proliferation and DDP resistance in A549 cells, and knockdown of miR-424-5p did the opposite. Knockdown of miR-424-5p enhanced DDP restriction on tumor weight and volume. Moreover, SOCS5 and SOCS56 (SOCS5/6) were downstream targets of miR-424-5p. miR-424-5p down-regulated SOCS5/6 expression to activate JAK2/STAT3 and PI3K/AKT pathways. Notably, tumor protein p53 (TP53) is a transcription factor for the miR-424-5p host gene, as confirmed by the dual-luciferase reporter gene. Cellular and animal experiments indicated that TP53 limited the regulatory function of miR-424-5p on NSCLC growth, DDP resistance, and related molecules. Interestingly, miR-424-5p was markedly enriched in A549/DDP cell-derived exosomes than in A549 cell-derived exosomes, and TP53 down-regulated miR-424-5p expression in A549/DDP cell-derived exosomes. Conclusion: DDP-resistant cell-derived exosome miR-424-5p contributes...