Loss of miR-200c-3p promotes resistance to radiation therapy via the DNA repair pathway in prostate cancer.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-16 DOI:10.1038/s41419-024-07133-3
Maureen Labbé, Manon Chang, Benjamin Saintpierre, Franck Letourneur, Laurence de Beaurepaire, Joëlle Véziers, Sophie Deshayes, Marine Cotinat, Jean-François Fonteneau, Christophe Blanquart, Vincent Potiron, Stéphane Supiot, Delphine Fradin
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Abstract

Radiotherapy represents a major curative treatment for prostate cancer (PCa), but some patients will develop radioresistance (RR) and relapse. The underlying mechanisms remain poorly understood, and miRNAs might be key players in the acquisition and maintenance of RR. Through their encapsulation in small extracellular vesicles (EVs), they can also be relevant biomarkers of radiation response. Using next-generation sequencing, we found that miR-200c-3p was downregulated in PCa RR cells and in their small EVs due to a gain of methylation on its promoter during RR acquisition. We next showed that its exogenous overexpression restores the radiosensitivity of RR cells by delaying DNA repair through the targeting of HP1α. Interestingly, we also observed downregulation of miR-200c-3p expression by DNA methylation in radiation-resistant lung and breast cancer cell lines. In summary, our study demonstrates that the downregulation of miR-200c-3p expression in PCa cells and in their small EVs could help distinguish radioresistant from sensitive tumor cells. This miRNA targets HP1α to delay DNA repair and promote cell death.

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miR-200c-3p的缺失会通过DNA修复途径促进前列腺癌对放射治疗的耐受性。
放疗是治疗前列腺癌(PCa)的主要方法,但有些患者会产生放射抗性(RR)并复发。人们对其潜在机制仍知之甚少,而 miRNA 可能是获得和维持 RR 的关键因素。miRNA被包裹在小的细胞外囊泡(EVs)中,因此也可以成为辐射反应的相关生物标志物。通过使用新一代测序技术,我们发现 miR-200c-3p 在 PCa RR 细胞及其小型 EVs 中下调,原因是其启动子在 RR 获得过程中发生了甲基化。接下来我们发现,miR-200c-3p 的外源过表达通过靶向 HP1α 而延迟 DNA 修复,从而恢复了 RR 细胞的放射敏感性。有趣的是,我们还在耐辐射肺癌和乳腺癌细胞系中观察到 DNA 甲基化对 miR-200c-3p 表达的下调作用。总之,我们的研究表明,miR-200c-3p 在 PCa 细胞及其小 EVs 中的表达下调有助于区分抗放射和敏感的肿瘤细胞。这种miRNA靶向HP1α,延迟DNA修复,促进细胞死亡。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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