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探索腹膜假黏液瘤中的RNA生物学，揭示剪接失调为一种新的、可靶向的分子弱点

Exploring RNA biology in pseudomyxoma peritonei uncovers splicing dysregulation as a novel, targetable molecular vulnerability

原文发布日期：2025-04-29

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探索腹膜假黏液瘤中的RNA生物学，揭示剪接失调为一种新的、可靶向的分子弱点

Exploring RNA biology in pseudomyxoma peritonei uncovers splicing dysregulation as a novel, targetable molecular vulnerability

原文发布日期：2025-04-29

英文摘要：

Pseudomyxoma peritonei (PMP) is a rare neoplasm coursing with uncontrollable mucus accumulation, with a high relapse rate. RNA biology processes have emerged as new players in cancer development and progression, nevertheless their role in PMP remains unknown. In this study, we aimed to examine RNA-regulatory machineries in PMP and their potential contribution to this disease progression. We analyzed 62 splicing-related genes, 27 RNA exosome and 21 nonsense-mediated decay genes, in a cohort of 29 patients using a microfluidic array, comparing tumor and control/reference tissues, together with external RNA-seq and proteomic data. Our results revealed a profound dysregulation of key components, which correlated to relevant clinical parameters and enabled to distinguish between tumor and control tissues. In vitro splicing inhibition using Pladienolide-B, as well as the modulation of specific splicing factors, reduced aggressiveness parameters, enhanced the effect of clinically used drugs, and revealed a strong correlation between dysregulated genes and key cancer-related genes. This inhibition also affected mucin secretion and mucin variants production. Collectively, our findings provide the first evidence for dysregulation of the genes of pivotal RNA-regulatory processes in PMP, implying that these targetable mechanisms may be functionally altered and play a role in the disease. Hence, a thorough understanding of its RNA biology could aid in the discovery of new clinically actionable vulnerabilities in this rare disease.

摘要翻译：

假性黏液瘤（PMP）是一种以黏液不可控积聚为特征的罕见肿瘤，具有高复发率。RNA生物学过程在癌症发生发展中的作用日益受到关注，但其在PMP中的功能仍属未知。本研究旨在探究PMP中的RNA调控机制及其对疾病进展的潜在影响。我们通过微流控阵列技术对29例患者的肿瘤组织与对照/参考组织进行分析，检测了62个剪接相关基因、27个RNA外泌体基因和21个无义介导衰变基因，并结合外部RNA测序与蛋白质组学数据。结果显示关键组分的显著失调与相关临床参数存在关联，并能有效区分肿瘤与正常组织。使用Pladienolide-B进行体外剪接抑制及特定剪接因子的调控，可降低肿瘤侵袭参数，增强临床药物的疗效，并发现失调基因与癌症关键基因存在强相关性。这种抑制同时影响黏蛋白分泌及其变异体的产生。我们的研究首次证明PMP中关键RNA调控过程基因存在失调现象，表明这些可靶向机制可能发生功能性改变并在疾病中发挥作用。因此，深入理解其RNA生物学特性有助于发现这种罕见疾病中具有临床可行性的新治疗靶点。