结直肠癌（CRC）在全球范围内日益受到关注，其发病率和死亡率不断上升，从而造成了巨大的健康负担。本研究深入探讨核受体亚家族 3 C 组成员 1 (NR3C1) 在 CRC 转移中的作用并探讨相关机制。通过全面的生物信息学分析，NR3C1 作为结直肠癌中表达水平降低的基因出现。 CRC 组织和细胞中 NR3C1 低表达模式的观察结果证实了这一发现。此外，涉及 NR3C1 敲低的实验显示，体外结直肠癌细胞的增殖、迁移和侵袭加剧。通过尾静脉或盲肠末端注射人 HCT116 细胞建立的小鼠异种移植肿瘤模型的后续评估表明，NR3C1 敲低后，肿瘤转移至肺和肝的能力分别减少。从功能上讲，NR3C1（糖皮质激素受体）通过与其启动子区域结合来抑制 SET 结合蛋白 1 (SETBP1) 的转录。值得注意的是，小鼠双分钟 4 (MDM4) 被确定为 NR3C1 的上游调节因子，通过泛素化依赖性蛋白酶体降解协调其下调。进一步的研究表明，SETBP1 敲除抑制了 CRC 细胞的迁移和侵袭以及上皮细胞向间质细胞的转变，从而阻碍了小鼠模型中的体内转移。相反，MDM4 的上调加剧了 CRC 细胞的转移表型，而 NR3C1 的额外上调则减轻了这种倾向。总之，本研究阐明了一个级联反应，其中 MDM4 介导的 NR3C1 泛素化使 SETBP1 转录激活，从而推动 CRC 细胞的传播。© 2024。作者获得 Springer Nature B.V. 的独家许可。

Colorectal cancer (CRC) presents a growing concern globally, marked by its escalating incidence and mortality rates, thus imposing a substantial health burden. This investigation delves into the role of nuclear receptor subfamily 3 group C member 1 (NR3C1) in CRC metastasis and explores the associated mechanism. Through a comprehensive bioinformatics analysis, NR3C1 emerged as a gene with diminished expression levels in CRC. This finding was corroborated by observations of a low-expression pattern of NR3C1 in both CRC tissues and cells. Furthermore, experiments involving NR3C1 knockdown revealed an exacerbation of proliferation, migration, and invasion of CRC cells in vitro. Subsequent assessments in mouse xenograft tumor models, established by injecting human HCT116 cells either through the tail vein or at the cecum termini, demonstrated a reduction in tumor metastasis to the lung and liver, respectively, upon NR3C1 knockdown. Functionally, NR3C1 (glucocorticoid receptor) suppressed SET binding protein 1 (SETBP1) transcription by binding to its promoter region. Notably, mouse double minute 4 (MDM4) was identified as an upstream regulator of NR3C1, orchestrating its downregulation via ubiquitination-dependent proteasomal degradation. Further investigations unveiled that SETBP1 knockdown suppressed migration and invasion, and epithelial to mesenchymal transition of CRC cells, consequently impeding in vivo metastasis in murine models. Conversely, upregulation of MDM4 exacerbated the metastatic phenotype of CRC cells, a propensity mitigated upon additional upregulation of NR3C1. In summary, this study elucidates a cascade wherein MDM4-mediated ubiquitination of NR3C1 enables the transcriptional activation of SETBP1, thereby propelling the dissemination of CRC cells.© 2024. The Author(s), under exclusive licence to Springer Nature B.V.