Department of Molecular Bone Biology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.
Department of Clinical Oral Oncology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.
Oncogene. 2022 Jan;41(5):683-691. doi: 10.1038/s41388-021-02120-w. Epub 2021 Nov 22.
Osteosarcoma (OS) in human patients is characterized by genetic alteration of TP53. Osteoprogenitor-specific p53-deleted mice (OS mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown. In this study, we detected prominent RUNX3/Runx3 expression in human and mouse p53-deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in the Myc promoter, in a manner dependent on p53 deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity of p53-deficient OS cells and effectively suppressed OS development in OS mice. Furthermore, Runx inhibitors exerted therapeutic effects on OS mice. Together, these results show that p53 deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression.
人类患者的骨肉瘤（OS）的特征在于 TP53 的遗传改变。成骨细胞特异性 p53 缺失小鼠（OS 小鼠）已被广泛用于研究骨肉瘤发生的过程。然而，p53 失活导致 OS 发展的分子机制在很大程度上仍然未知。在这项研究中，我们在人和小鼠 p53 缺陷型 OS 中检测到明显的 RUNX3/Runx3 表达。Myc 通过 mR1 异常上调，mR1 是 Myc 启动子中的一个公认的 Runx 位点，这种方式依赖于 p53 的缺失。通过破坏 mR1 或敲低 Runx3 降低 Myc 水平，可降低 p53 缺陷型 OS 细胞的致瘤性，并有效抑制 OS 小鼠的 OS 发展。此外，Runx 抑制剂对 OS 小鼠具有治疗作用。总之，这些结果表明，p53 缺失通过允许 Runx3 诱导致癌性 Myc 表达促进人类和小鼠的骨肉瘤发生。
