胰腺导管腺癌（PDAC）是最致命的癌症之一，这凸显了深入生物学研究的迫切需要。选择性 RNA 剪接失调现象是癌症（包括 PDAC）的常见标志，为理解和开发诊断和治疗工具提供了新途径。我们的研究重点是 EIF4A3（与 RNA 剪接密切相关的外显子连接复合物的核心成分）及其在 PDAC 中的作用。 EIF4A3 在 PDAC 组织中过度表达，与恶性肿瘤的临床参数和较差的患者生存率相关。从机制上讲，对 PDAC RNA-seq 数据的探索揭示了 EIF4A3 与多种恶性肿瘤过程的联系，与其与关键分子途径的关联一致。 EIF4A3 体外靶向减少了肿瘤的基本功能特征，如增殖、迁移、集落形成和球体形成，而其体内靶向则减少了肿瘤生长。 RNA-seq 分析显示，PDAC 细胞系中的 EIF4A3 沉默严重改变了其转录和剪接体景观，表明 EIF4A3 在维持 RNA 稳态中发挥着作用。我们的结果表明，PDAC 中的 EIF4A3 失调对 RNA 生物学具有多效性调节作用，影响关键的细胞功能。这为探索其作为这种致命癌症的新型生物标志物和可行靶标候选物的潜力铺平了道路。© 2024。作者。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, underscoring the urgent need for in-depth biological research. The phenomenon of alternative RNA splicing dysregulation is a common hallmark in cancer, including PDAC, presenting new avenues for understanding and developing diagnostic and therapeutic tools. Our research focuses on EIF4A3, a core component of the Exon Junction Complex intimately linked to RNA splicing, and its role in PDAC. EIF4A3 is overexpressed in PDAC tissue and associated to clinical parameters of malignancy and poorer patient survival. Mechanistically, exploration of PDAC RNA-seq data unveiled the link of EIF4A3 to diverse malignancy processes, consistent with its association to key molecular pathways. EIF4A3 targeting in vitro decreased essential functional tumor features such as proliferation, migration, colony formation and sphere formation, while its in vivo targeting reduced tumor growth. EIF4A3 silencing in PDAC cell lines severely altered its transcriptional and spliceosomic landscapes, as shown by RNA-seq analyses, suggesting a role for EIF4A3 in maintaining RNA homeostasis. Our results indicate that EIF4A3 dysregulation in PDAC has a pleiotropic regulatory role on RNA biology, influencing key cellular functions. This paves the way to explore its potential as novel biomarker and actionable target candidate for this lethal cancer.© 2024. The Author(s).