Wang Ting, Wang Shan, Wang Tao, Jia Lintao, Nan Gang, Wang Liang
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University Xi'an 710032, Shaanxi, China.
Institute of Basic Translational Medicine, Xi'an Medical University Xi'an 710021, Shaanxi, China.
Am J Cancer Res. 2024 Jun 15;14(6):2868-2880. doi: 10.62347/CVAY8707. eCollection 2024.
Medulloblastoma (MB) is a severe malignancy of the central nervous system that predominantly occurs in the cerebellum of children. Overactivation of the sonic hedgehog (Shh) signaling pathway is the primary cause of the development and progression of Shh subtype MB, although the detailed mechanisms underlying this process remain largely elusive. In this study, we discovered that Shh can promote proliferation in MB cells through non-canonical Hedgehog signaling. This involves Shh binding to Patched 1, disrupting its interaction with Cyclin B1, allowing for nuclear translocation of Cyclin B1, and inducing the activation of genes involved in cell division. Furthermore, we observed that deregulation of Cdc14B leads to the stabilization of the Cyclin B1/CDK1 complex in MB cells through activating Cdc25C, a phosphatase known to help maintain Cyclin B1 stability. Our findings highlight the role of Cdc14B/Cdc25C/CDK1/Cyclin B1 in mediating Hedgehog signaling-driven pathogenesis in MB and have implications for identifying potential therapeutic targets.
髓母细胞瘤（MB）是中枢神经系统的一种严重恶性肿瘤，主要发生于儿童小脑。音猬因子（Shh）信号通路的过度激活是Shh亚型MB发生发展的主要原因，尽管这一过程的详细机制仍 largely elusive。在本研究中，我们发现Shh可通过非经典Hedgehog信号促进MB细胞增殖。这涉及Shh与Patched 1结合，破坏其与细胞周期蛋白B1（Cyclin B1）的相互作用，使Cyclin B1发生核转位，并诱导参与细胞分裂的基因激活。此外，我们观察到细胞分裂周期蛋白14B（Cdc14B）失调通过激活Cdc25C（一种已知有助于维持Cyclin B1稳定性的磷酸酶）导致MB细胞中Cyclin B1/细胞周期蛋白依赖性激酶1（CDK1）复合物稳定。我们的研究结果突出了Cdc14B/Cdc25C/CDK1/Cyclin B1在介导Hedgehog信号驱动的MB发病机制中的作用，并对识别潜在治疗靶点具有启示意义。
