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通过 microRNA 介导的 DNA 损伤调控对 FOLFIRINOX 治疗胰腺癌细胞敏感性的调节。

Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage.

机构信息

Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.

TIGEM - Telethon Institute of Genetics and Medicine, Naples, Italy.

出版信息

Nat Commun. 2021 Nov 18;12(1):6738. doi: 10.1038/s41467-021-27099-6.

DOI:10.1038/s41467-021-27099-6
PMID:34795259
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8602334/
Abstract

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.

摘要

FOLFIRINOX（氟尿嘧啶、奥沙利铂、伊立替康的联合化疗）为胰腺导管腺癌（PDAC）患者提供了最佳的临床获益。在这项研究中，我们探索了 microRNA（miRNA）作为化疗敏感性调节剂的作用，以确定潜在的反应生物标志物。我们发现，41 种和 84 种 microRNA 抑制剂分别增强了 Capan1 和 MiaPaCa2 PDAC 细胞的敏感性。其中包括我们在进一步的 PDAC 细胞系中验证的 MIR1307 抑制剂。与对照 PDAC 细胞相比，MIR1307 敲除（MIR1307KO）细胞中的化疗诱导细胞凋亡和 DNA 损伤积累更高，而 MIR1307KO 细胞中 MIR1307 的重新表达挽救了这些作用。我们通过内源性 Argonaute 结合 RNA 的共价连接交联免疫沉淀检测鉴定了 MIR1307 与 CLIC5 mRNA 的结合。我们在 MIR1307 缺失的体内模型中验证了这些发现。在接受 FOLFIRONX 化疗的 PDAC 患者的试点队列中，循环 MIR1307 与临床结果相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/686b1278d7d7/41467_2021_27099_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/6f3997e440a1/41467_2021_27099_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/9eda2e0ef00f/41467_2021_27099_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/85c6dff2af99/41467_2021_27099_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/686b1278d7d7/41467_2021_27099_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/3badefe5cb58/41467_2021_27099_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/7c076dfd4e91/41467_2021_27099_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/95eb3d6b54a5/41467_2021_27099_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/6f3997e440a1/41467_2021_27099_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/9eda2e0ef00f/41467_2021_27099_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/92576f308420/41467_2021_27099_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/85c6dff2af99/41467_2021_27099_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ead8/8602334/686b1278d7d7/41467_2021_27099_Fig8_HTML.jpg

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