Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Mol Cancer Res. 2024 Jan 2;22(1):29-40. doi: 10.1158/1541-7786.MCR-23-0229.
Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95-3p/miR-95-5p, miR-124-3p, and members of the miR-17∼92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124-3p and members of the miR-17∼92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124-3p, and IHC studies demonstrated that ASCL1-positive LUADs are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell-cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124-3p could modulate gene expression, providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive LUADs.
Our study revealed unique miRNA profiles of ASCL1-positive LUADs and identified ASCL1-regulated miRNAs with functional relevance.
Achaete-scute 家族 bHLH 转录因子 1（ASCL1）是一种参与神经内分泌分化的主转录因子。ASCL1 在大约 10%的肺腺癌（LUAD）中表达，并发挥促肿瘤作用。在这里，我们探索了 ASCL1 阳性 LUAD 中的 miRNA 图谱，并确定了与 ASCL1 表达密切相关的几种 miRNA，包括 miR-375、miR-95-3p/miR-95-5p、miR-124-3p 和 miR-17∼92 家族成员。与小细胞肺癌类似，ASCL1 阳性 LUAD 中 Yes1 相关转录调节剂（YAP1），一个代表 miR-375 的靶基因，受到抑制。在细胞培养模型中进行 ASCL1 敲低和 miRNA 谱分析后，进一步表明 ASCL1 正向调节 miR-124-3p 和 miR-17∼92 家族成员。综合转录组学分析鉴定出 ZFP36 环指蛋白样 1（ZFP36L1）为 miR-124-3p 的靶基因，免疫组织化学研究表明 ASCL1 阳性 LUAD 与低水平的 ZFP36L1 蛋白水平相关。细胞培养研究表明，过表达 ZFP36L1 可抑制细胞增殖、存活和细胞周期进程。此外，ZFP36L1 负调控包括 E2F 转录因子 1（E2F1）和蜗牛家族转录抑制因子 1（SNAI1）在内的多个基因。总之，我们的研究揭示了通过 ASCL1 调节的 miR-124-3p 抑制 ZFP36L1 的机制，这为 ASCL1 介导的 miRNA 调节塑造 ASCL1 阳性 LUAD 的分子特征提供了证据。
我们的研究揭示了 ASCL1 阳性 LUAD 的独特 miRNA 图谱，并确定了具有功能相关性的 ASCL1 调节的 miRNA。
