Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
Sci Rep. 2023 Oct 29;13(1):18546. doi: 10.1038/s41598-023-45833-6.
We elucidated the mechanism through which the reduced expression of miR-152 leads to the overexpression of its target cyclin-dependent kinase-5 activator 1 (CDK5R1) in Ewing's sarcoma (ES) cells and the role of this mechanism in the proliferation of ES cells. To explore possible oncogenic factors in ES, we conducted microarray-based investigation and profiled the changes in miRNA expression and their effects on downstream mRNAs in five ES cell lines and human mesenchymal stem cells (hMSCs). miR-152 was significantly downregulated, while cyclin-dependent kinase-5 activator 1 (CDK5R1) expression was significantly upregulated in all tested ES cells as compared to hMSCs. The overexpression of CDK5R1 led to the activation of CDK5, enabling the phosphorylation of retinoblastoma protein and persistent overexpression of CCNE. Moreover, miR-152 suppressed cell proliferation via cell cycle retardation, and its upregulation reduced tumor size and CCNE expression in tumor tissues. The overexpression of cyclin E (CCNE) has been detected in ES cells, but the detailed mechanisms have not been previously elucidated. These findings identify the miR152-CDK5R1 signaling axis as a critical mechanism for tumorigenesis that may serve as a new therapeutic target in Ewing's sarcoma. We believe that our results will aid in the development of effective treatment strategies for patients with ES.
我们阐明了机制，即 miR-152 的表达减少导致其靶标细胞周期蛋白依赖性激酶 5 激活物 1（CDK5R1）在尤文肉瘤（ES）细胞中的过度表达，以及该机制在 ES 细胞增殖中的作用。为了探索 ES 中可能的致癌因素，我们进行了基于微阵列的调查，并对五种 ES 细胞系和人间充质干细胞（hMSC）中的 miRNA 表达变化及其对下游 mRNA 的影响进行了分析。与 hMSC 相比，miR-152 在所有测试的 ES 细胞中均显著下调，而细胞周期蛋白依赖性激酶 5 激活物 1（CDK5R1）的表达则显著上调。CDK5R1 的过表达导致 CDK5 的激活，使视网膜母细胞瘤蛋白磷酸化和 CCNE 的持续过表达。此外，miR-152 通过细胞周期阻滞抑制细胞增殖，上调 miR-152 可减少肿瘤组织中的肿瘤大小和 CCNE 表达。CCNE 的过表达已在 ES 细胞中检测到，但详细机制尚未阐明。这些发现确定了 miR152-CDK5R1 信号轴作为肿瘤发生的关键机制，可能成为尤文肉瘤的新治疗靶点。我们相信，我们的研究结果将有助于为 ES 患者开发有效的治疗策略。
