MYC 通过减弱 TP53 诱导的 microRNA-34 表达导致多发性骨髓瘤进展。

MYC Causes Multiple Myeloma Progression via Attenuating TP53-Induced MicroRNA-34 Expression.

机构信息

Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi 371-8510, Japan.

Laboratory of Mucosal Ecosystem Design, The Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8510, Japan.

出版信息

Genes (Basel). 2022 Dec 29;14(1):100. doi: 10.3390/genes14010100.

DOI:10.3390/genes14010100

PMID:36672841

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9859619/

Abstract

MicroRNAs (miRNAs and miRs) are small (19-25 base pairs) non-coding RNAs with the ability to modulate gene expression. Previously, we showed that the miR-34 family is downregulated in multiple myeloma (MM) as the cancer progressed. In this study, we aimed to clarify the mechanism of miRNA dysregulation in MM. We focused particularly on the interaction between MYC and the TP53-miR34 axis because there is a discrepancy between increased TP53 and decreased miR-34 expressions in MM. Using the nutlin-3 or Tet-on systems, we caused wild-type (WT) p53 protein accumulation in human MM cell lines (HMCLs) and observed upregulated miR-34 expression. Next, we found that treatment with an Myc inhibitor alone did not affect miR-34 expression levels, but when it was coupled with p53 accumulation, miR-34 expression increased. In contrast, forced MYC activation by the MYC-ER system reduced nutlin-3-induced miR-34 expression. We also observed that TP53 and MYC were negatively correlated with mature miR-34 expressions in the plasma cells of patients with MM. Our results suggest that MYC participates in the suppression of p53-dependent miRNA expressions. Because miRNA expression suppresses tumors, its inhibition leads to MM development and malignant transformation.

摘要

MicroRNAs (miRNAs and miRs) 是具有调节基因表达能力的小（19-25 个碱基对）非编码 RNA。此前，我们发现 miR-34 家族在多发性骨髓瘤（MM）进展过程中下调。在这项研究中，我们旨在阐明 MM 中 miRNA 失调的机制。我们特别关注 MYC 和 TP53-miR34 轴之间的相互作用，因为在 MM 中存在 TP53 增加和 miR-34 表达减少之间的差异。使用 nutlin-3 或 Tet-on 系统，我们在人多发性骨髓瘤细胞系（HMCL）中引起野生型（WT）p53 蛋白积累，并观察到 miR-34 表达上调。接下来，我们发现单独使用 Myc 抑制剂治疗不会影响 miR-34 表达水平，但当与 p53 积累结合时，miR-34 表达增加。相比之下，MYC-ER 系统的强制 MYC 激活降低了 nutlin-3 诱导的 miR-34 表达。我们还观察到在 MM 患者浆细胞中，TP53 和 MYC 与成熟 miR-34 表达呈负相关。我们的结果表明，MYC 参与抑制 p53 依赖性 miRNA 表达。因为 miRNA 表达抑制肿瘤，其抑制导致 MM 发展和恶性转化。