Resistance to radiation enhances metastasis by altering RNA metabolism

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-10-17 DOI:10.1126/sciadv.adx3050

Ayush Kumar, Kensei Kishimoto, Hira L. Goel, Christi A. Silva, Rui Li, Brendan Pacheco, Lihua J. Zhu, William A. Flavahan, Arthur M. Mercurio

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Abstract

The cellular programs that mediate therapy resistance are often important drivers of metastasis, a phenomenon that needs to be understood better to improve screening and treatment options for patients with cancer. Although this issue has been studied extensively for chemotherapy, less is known about a causal link between resistance to radiation therapy and metastasis. We investigated this problem in triple-negative breast cancer and established that radiation-resistant tumor cells have enhanced metastatic capacity. Resistance to radiation increases the expression of integrin β3 (ITGB3), which promotes enhanced migration and invasion. Bioinformatic analysis and subsequent experimentation revealed an enrichment of RNA metabolism pathways that stabilize ITGB3 transcripts. Specifically, the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL), whose expression is regulated by Nrf2, mediates the formation of circular RNAs that sponge the family of let-7 microRNAs that target ITGB3. Collectively, our findings identify a mechanism of radiation-induced metastasis that is driven by alterations in RNA metabolism.

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对辐射的抵抗通过改变RNA代谢来促进转移

介导治疗耐药的细胞程序通常是转移的重要驱动因素，这一现象需要更好地了解，以改善癌症患者的筛查和治疗选择。尽管这一问题已经在化疗中得到了广泛的研究，但对放疗耐药与转移之间的因果关系知之甚少。我们在三阴性乳腺癌中研究了这一问题，并确定耐辐射肿瘤细胞具有增强的转移能力。对辐射的抵抗增加了整合素β3 （ITGB3）的表达，促进了迁移和侵袭。生物信息学分析和随后的实验揭示了稳定ITGB3转录物的RNA代谢途径的富集。具体来说，RNA结合蛋白异质核核糖核蛋白L （HNRNPL）的表达受Nrf2调节，它介导环状RNA的形成，这些环状RNA会吞噬靶向ITGB3的let-7 microrna家族。总的来说，我们的发现确定了一种由RNA代谢改变驱动的辐射诱导转移的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.