胰腺导管腺癌（PDAC）是一种高度致命的癌症，其特点是诊断晚和治疗反应差。手术是唯一的治疗方法，仅适用于早期诊断的患者。目前的疗法效果有限，会引起严重的毒性，并且对总体生存率的改善微乎其微。对 PDAC 中剪接机制改变的理解仍然不完整。在这里，我们全面检查了 59 个剪接机制组件，揭示了前 mRNA 加工因子 8 (PRPF8) 和 RNA 结合基序蛋白 X-linked (RBMX) 的失调。它们的表达下调与不良预后和恶性肿瘤特征（包括肿瘤分期、侵袭和转移）有关，并与较差的生存率和关键 PDAC 基因的突变有关。在胰腺癌细胞系中对这些剪接因子进行实验调节，将其表达恢复至非肿瘤水平，并导致与肿瘤相关的关键特征减少。这些结果提供了证据，表明 PDAC 中的剪接机制发生了改变，其中 PRPF8 和 RBMX 成为候选的可行治疗靶点。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, characterized by late diagnosis and poor treatment response. Surgery is the only curative approach, only available to early-diagnosed patients. Current therapies have limited effects, cause severe toxicities, and minimally improve overall survival. Understanding of splicing machinery alterations in PDAC remains incomplete. Here, we comprehensively examined 59 splicing machinery components, uncovering dysregulation in pre-mRNA processing factor 8 (PRPF8) and RNA-binding motif protein X-linked (RBMX). Their downregulated expression was linked to poor prognosis and malignancy features, including tumor stage, invasion and metastasis, and associated with poorer survival and the mutation of key PDAC genes. Experimental modulation of these splicing factors in pancreatic cancer cell lines reverted their expression to non-tumor levels and resulted in decreased key tumor-related features. These results provide evidence that the splicing machinery is altered in PDAC, wherein PRPF8 and RBMX emerge as candidate actionable therapeutic targets.© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.