Department of Oncology, Ganzhou City People's Hospital, Ganzhou, China.
Chem Biol Drug Des. 2023 Oct;102(4):815-827. doi: 10.1111/cbdd.14293. Epub 2023 Jul 27.
Diaminodichoroplatinum (DDP) resistance of tumor cells is the culprit of nasopharyngeal carcinoma (NPC) treatment failure. MicroRNA-577 is lowly expressed in NPC tissues, but relevant mechanism is poorly studied. Therefore, this study investigated the role of microRNA-577 in NPC cells with DDP resistance and its mechanism. DDP-resistant NPC cells were established by treatment with DDP at increased concentrations (2, 4, 6, 8, or 10 μg/mL). MicroRNA-577 and EIF5A2 mRNA expressions were detected by qRT-PCR. Cell biological behaviors were assessed via cell function experiments. Expressions of epithelial mesenchymal transformation (EMT)-related proteins were quantified by western blot. The targeting relationship between eukaryotic translation initiation factor 5A2 (EIF5A2) and microRNA-577 was verified through dual-luciferase reporter assay. The tumor volume and weight were measured after subcutaneous tumorigenesis in mice. As observed from the results, microRNA-577 expression was reduced in NPC cells and DDP-resistant NPC cells. Up-regulated microRNA-577 suppressed the malignant behaviors and EMT of DDP-resistant NPC cells, and facilitated cell apoptosis. MicroRNA-577 targeted EIF5A2, and overexpressed EIF5A2 reversed the above effects of up-regulated microRNA-577 on DDP-resistant NPC cells. Besides, EIF5A2 positively regulated TGF-β signaling pathway, and TGF-β treatment offset the promoting effects of EIF5A2 silencing on apoptosis of DDP-resistant NPC cells. Up-regulated microRNA-577 suppressed the proliferation of DDP-resistant NPC cells, and down-regulated the levels of EIF5A2 and TGF-β as well as EMT in vivo. Collectively, microRNA-577/EIF5A2 axis hinders the EMT progression through the blockage of TGF-β signaling pathway, so as to inhibit the proliferation of DDP-resistant NPC.
肿瘤细胞的二氨基二氯铂（DDP）耐药性是鼻咽癌（NPC）治疗失败的罪魁祸首。miR-577 在 NPC 组织中低表达，但相关机制研究甚少。因此，本研究探讨了 miR-577 在具有 DDP 耐药性的 NPC 细胞中的作用及其机制。采用浓度递增的 DDP（2、4、6、8 或 10μg/mL）处理建立 DDP 耐药 NPC 细胞。采用 qRT-PCR 检测 miR-577 和 EIF5A2mRNA 的表达。通过细胞功能实验评估细胞生物学行为。采用 Western blot 定量检测上皮间质转化（EMT）相关蛋白的表达。通过双荧光素酶报告实验验证真核翻译起始因子 5A2（EIF5A2）与 miR-577 的靶向关系。在小鼠皮下成瘤后测量肿瘤体积和重量。结果显示，miR-577 在 NPC 细胞和 DDP 耐药 NPC 细胞中表达降低。上调 miR-577 抑制 DDP 耐药 NPC 细胞的恶性行为和 EMT，并促进细胞凋亡。miR-577 靶向 EIF5A2，过表达 EIF5A2 逆转了上调 miR-577 对 DDP 耐药 NPC 细胞的上述作用。此外，EIF5A2 正向调控 TGF-β 信号通路，TGF-β 处理抵消了 EIF5A2 沉默对 DDP 耐药 NPC 细胞凋亡的促进作用。上调 miR-577 抑制 DDP 耐药 NPC 细胞的增殖，下调 EIF5A2、TGF-β 水平及体内 EMT。综上，miR-577/EIF5A2 轴通过阻断 TGF-β 信号通路抑制 EMT 进展，从而抑制 DDP 耐药 NPC 的增殖。
