Transcriptional factor Forkhead box M1 (FOXM1) plays an important role in pancreatic ductal adenocarcinoma (PDAC) development and progression. The molecular mechanisms underlying its dysregulation remain unclear. We identified and functionally validated the microRNAs (miRNAs) that critically regulate FOXM1 expression in PDAC. The expression levels of miRNA-23a (miR-23a-3p and -5p) were altered in PDAC cell lines and their effects on FOXM1 signaling and cell proliferation and migration and tumorigenesis were examined in vitro and in vivo using mouse PDAC models. Compared with non-tumor pancreatic tissues, PDAC tissues and cell lines exhibited significantly reduced levels of miR-23a expression. Reduced miR-23a expression and concomitant increase in FOXM1 expression were also observed in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia, the major premalignant lesions of PDAC. Transgenic expression of miR-23a reduced the expression of FOXM1 and suppressed cell proliferation and migration in PDAC cells, whereas the inhibitors of miR-23a did the opposite. Loss or reduced levels of miR-23a increased the levels of FOXM1 expression, while increased expression of FOXM1 down-regulated miR-23a expression, suggesting that miR-23a and FOXM1 were mutual negative regulators of their expression in PDAC cells. Therefore, the miR-23a/FOXM1 signaling axis is important in PDAC initiation and progression and could serve as an interventional or therapeutic target for patients with early or late stages of PDAC.

转录因子 Forkhead box M1 (FOXM1) 在胰腺导管腺癌 (PDAC) 的发生和进展中发挥着重要作用。其失调的分子机制仍不清楚。我们鉴定并功能验证了在 PDAC 中关键调节 FOXM1 表达的 microRNA (miRNA)。PDAC 细胞系中 miRNA-23a（miR-23a-3p 和 -5p）的表达水平发生改变，并使用小鼠 PDAC 模型在体外和体内检查了它们对 FOXM1 信号传导、细胞增殖、迁移和肿瘤发生的影响。与非肿瘤胰腺组织相比，PDAC组织和细胞系的miR-23a表达水平显着降低。在腺泡导管化生和胰腺上皮内瘤变（PDAC 的主要癌前病变）中也观察到 miR-23a 表达减少和 FOXM1 表达随之增加。miR-23a的转基因表达降低了FOXM1的表达并抑制了PDAC细胞中的细胞增殖和迁移，而miR-23a的抑制剂则起到相反的作用。miR-23a的丢失或水平降低会增加FOXM1的表达水平，而FOXM1的表达增加会下调miR-23a的表达，表明miR-23a和FOXM1在PDAC细胞中是它们表达的相互负调节因子。因此，miR-23a/FOXM1信号轴在PDAC的启动和进展中非常重要，可以作为早期或晚期PDAC患者的介入或治疗靶点。