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外泌体miR-664a-5p作为前列腺癌中PARP抑制剂反应的治疗靶点生物标志物。

Exosomal miR-664a-5p as a therapeutic target biomarker for PARP inhibitor response in prostate cancer.

作者信息

Kim Mee Young, Moon Hyong Woo, Jo Min Soo, Lee Ji Youl

机构信息

Department of Urology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea Seoul, Republic of Korea.

Catholic Prostate Institute, The Catholic University of Korea Seoul, Republic of Korea.

出版信息

Am J Cancer Res. 2024 Aug 25;14(8):3789-3799. doi: 10.62347/QYZS2620. eCollection 2024.

Abstract

This study investigated the role of urinary exosomal miR-664a-5p as a potential therapeutic target in prostate cancer (PCa). Small RNA sequencing of urinary exosomes from PCa patients with different responses to PARP inhibitors revealed that miR-664a-5p was significantly upregulated in responsive patients. Overexpression of miR-664a-5p enhanced the sensitivity of PCa cells to PARP inhibitors by directly targeting FOXM1, a transcription factor involved in DNA damage repair, leading to the downregulation of DNA damage response genes. Combined treatment with miR-664a-5p and olaparib synergistically inhibited tumor growth in a PC-3 xenograft mouse model. These findings suggest that urinary exosomal miR-664a-5p is a potential therapeutic biomarker for PARP inhibitor response in PCa patients, and targeting FOXM1 via miR-664a-5p represents a promising strategy for enhancing PARP inhibitor efficacy in PCa treatment.

摘要

本研究调查了尿外泌体miR-664a-5p作为前列腺癌(PCa)潜在治疗靶点的作用。对PARP抑制剂有不同反应的PCa患者尿外泌体进行小RNA测序发现,miR-664a-5p在有反应的患者中显著上调。miR-664a-5p的过表达通过直接靶向参与DNA损伤修复的转录因子FOXM1,增强了PCa细胞对PARP抑制剂的敏感性,导致DNA损伤反应基因的下调。在PC-3异种移植小鼠模型中,miR-664a-5p与奥拉帕利联合治疗协同抑制肿瘤生长。这些发现表明,尿外泌体miR-664a-5p是PCa患者对PARP抑制剂反应的潜在治疗生物标志物,通过miR-664a-5p靶向FOXM1是增强PARP抑制剂在PCa治疗中疗效的一种有前景的策略。

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A Genetic Map of the Response to DNA Damage in Human Cells.人类细胞对 DNA 损伤反应的遗传图谱。
Cell. 2020 Jul 23;182(2):481-496.e21. doi: 10.1016/j.cell.2020.05.040. Epub 2020 Jul 9.

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