程序性细胞死亡 4 (PDCD4) 在多发性骨髓瘤 (MM) 发展中的作用仍不清楚。在这里，我们研究了它在 MM 中的作用和作用机制。生物信息分析表明，PDCD4 高表达的 MM 患者比 PDCD4 低表达的患者具有更高的总生存期。 PDCD4 表达促进 MM 细胞凋亡并抑制其体外活力和体内肿瘤生长。 RNA结合蛋白免疫沉淀测序分析表明，PDCD4与凋亡相关基因PIK3CB、组织蛋白酶Z（CTSZ）和X染色体连锁凋亡抑制剂（XIAP）的5'UTR结合。 PDCD4 敲除降低了细胞凋亡率，通过添加 PIK3CB、CTSZ 或 XIAP 抑制剂可以挽救细胞凋亡率。双荧光素酶报告基因测定证实了 PIK3CB 和 CTSZ 5' UTR 的内部核糖体进入位点 (IRES) 活性。 RNA Pull-down 测定证实了 PIK3CB 和 CTSZ 的 5' UTR 与 PDCD4 的结合，从而鉴定了特异性结合片段。 PDCD4 有望通过与 PIK3CB 和 CTSZ 5' UTR 中的 IRES 结构域结合并抑制其翻译来促进 MM 细胞凋亡。我们的研究结果表明，PDCD4 通过调节 PIK3CB、CTSZ 和 XIAP 的表达在 MM 发展中发挥重要作用，并突出了 MM 治疗的新潜在分子靶标。© 2024 美国实验生物学会联合会。

The role of programmed cell death 4 (PDCD4) in multiple myeloma (MM) development remains unknown. Here, we investigated its role and action mechanism in MM. Bioinformatic analysis indicated that patients with MM and high PDCD4 expression had higher overall survival than those with low PDCD4 expression. PDCD4 expression promoted MM cell apoptosis and inhibited their viability in vitro and tumor growth in vivo. RNA-binding protein immunoprecipitation sequencing analysis showed that PDCD4 is bound to the 5' UTR of the apoptosis-related genes PIK3CB, Cathepsin Z (CTSZ), and X-chromosome-linked apoptosis inhibitor (XIAP). PDCD4 knockdown reduced the cell apoptosis rate, which was rescued by adding PIK3CB, CTSZ, or XIAP inhibitors. Dual luciferase reporter assays confirmed the internal ribosome entry site (IRES) activity of the 5' UTRs of PIK3CB and CTSZ. An RNA pull-down assay confirmed binding of the 5' UTR of PIK3CB and CTSZ to PDCD4, identifying the specific binding fragments. PDCD4 is expected to promote MM cell apoptosis by binding to the IRES domain in the 5' UTR of PIK3CB and CTSZ and inhibiting their translation. Our findings suggest that PDCD4 plays an important role in MM development by regulating the expression of PIK3CB, CTSZ, and XIAP, and highlight new potential molecular targets for MM treatment.© 2024 Federation of American Societies for Experimental Biology.