Tenhaken Victoria, Seternes Ole-Morten, Cascorbi Ingolf, Bruckmueller Henrike
Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany.
Department of Pharmacy, UiT The Arctic University of Norway, Tromsø, 9037, Norway.
BMC Cancer. 2025 Jun 19;25(1):1020. doi: 10.1186/s12885-025-14434-z.
Aberrant changes in protein phosphorylation are a hallmark of cancer, often leading to hyperactivation of signalling pathways such as the mitogen activated protein kinase (MAPK) pathway. Although kinase inhibitors are successfully used in certain clinical indications, drug resistance remains a challenge, and alternative approaches to control phosphorylation-dependent oncogenic signalling are increasingly being considered. These include the modulation of negative regulators of oncogenic signalling pathways. The dual-specificity phosphatase 2 (DUSP2) is one of the essential negative regulators for the MAPK pathway, providing tight and efficient control of MAPKs under physiological conditions. However, in oncogenic contexts, negative feedback regulation is often impaired and the mechanisms controlling DUSP2 expression and function remain largely elusive. The aim of the present study was to investigate whether microRNA-mediated regulation of DUSP2 could contribute to an impairment of negative feedback regulation in cancer.
A combination of in silico target prediction, integrative analysis of pan-cancer microRNA and DUSP2 mRNA expression data as well as a literature search was applied to identify microRNAs potentially regulating DUSP2 expression in cancer context. Predicted interactions of microRNAs with the DUSP2 3'UTR were verified using reporter gene assays and functionally validated in a lymphoma cell model.
A comprehensive analysis of microRNA and DUSP2 mRNA expression data across 32 cancer types revealed significant inverse correlations between oncogenic microRNA clusters (miR-17-92, miR-106a-363, and miR-106b-25 cluster) and DUSP2 expression in various cancer types. Reporter gene assay analysis confirmed the interaction of miR-17-5p, miR-20a-5p, miR-20b-5p, miR-29b-3p, miR-93-5p, miR-106b-5p, miR-122-5p, miR-340-5p, miR-520a-3p, and miR-520c-3p with the DUSP2 mRNA 3'UTR. Furthermore, treatment of the lymphoma cell line WSU-DLCL2 with microRNA inhibitors for miR-17-5p, miR-20b-5p, or miR-106b-5p resulted in increased DUSP2 mRNA levels.
The results of this study indicate that microRNA-mediated regulation of DUSP2 in hematologic and solid cancers appears to be a plausible mechanism that contributes to the dysregulation of MAP kinase signaling pathways in cancer by impairing negative feedback regulation. The data provide a solid foundation for future studies to investigate the consequences of regulation of DUSP function in cancer in more depth.
蛋白质磷酸化的异常变化是癌症的一个标志，常常导致丝裂原活化蛋白激酶（MAPK）等信号通路的过度激活。尽管激酶抑制剂已成功应用于某些临床适应症，但耐药性仍然是一个挑战，因此人们越来越多地考虑采用其他方法来控制磷酸化依赖性致癌信号传导。这些方法包括调节致癌信号通路的负调节因子。双特异性磷酸酶2（DUSP2）是MAPK通路的重要负调节因子之一，在生理条件下对MAPK进行严格而有效的控制。然而，在致癌环境中，负反馈调节常常受损，控制DUSP2表达和功能的机制仍 largely 不清楚。本研究的目的是调查 microRNA 介导的 DUSP2 调节是否会导致癌症中负反馈调节的受损。
结合计算机靶标预测、泛癌 microRNA 和 DUSP2 mRNA 表达数据的综合分析以及文献检索，以鉴定在癌症背景下可能调节 DUSP2 表达的 microRNA。使用报告基因测定法验证 microRNA 与 DUSP2 3'UTR 的预测相互作用，并在淋巴瘤细胞模型中进行功能验证。
对 32 种癌症类型的 microRNA 和 DUSP2 mRNA 表达数据进行的综合分析显示，致癌 microRNA 簇（miR-17-92、miR-106a-363 和 miR-106b-25 簇）与各种癌症类型中 DUSP2 的表达之间存在显著的负相关。报告基因测定分析证实了 miR-17-5p、miR-20a-5p、miR-20b-5p、miR-29b-3p、miR-93-5p、miR-106b-5p、miR-122-5p、miR-340-5p、miR-520a-3p 和 miR-520c-3p 与 DUSP2 mRNA 3'UTR 的相互作用。此外，用 miR-17-5p、miR-20b-5p 或 miR-106b-5p 的 microRNA 抑制剂处理淋巴瘤细胞系 WSU-DLCL2 导致 DUSP2 mRNA 水平升高。
本研究结果表明，microRNA 介导的血液系统和实体癌中 DUSP2 的调节似乎是一种合理的机制，通过损害负反馈调节导致癌症中 MAP 激酶信号通路的失调。这些数据为未来更深入研究癌症中 DUSP 功能调节的后果提供了坚实的基础。
