细胞周期抑制蛋白E2F6和Cdc14B在Hedgehog信号驱动髓母细胞瘤发生中的作用

Medulloblastoma (MB) is the most common central nervous system malignancy for children. The activation of Hedgehog (Hh) signaling is pivotally involved in MB pathogenesis, the underlying mechanism of which remains largely elusive. Through expression-profile microarray, we found that the expression of the cell cycle inhibitor protein Cdc14b and the transcription factor E2F6 were significantly down-regulated in the mouse MB model induced by transgenic expression of the Hh receptor Smo. It is reported that Cdc14b modulates the expression of cell cycle dependent kinase inhibitor (CKI) by binding to p53, and that ectopic expression of E2F6 leads to accumulation of cells in S-phase, both of which prevent cells from entrying into the S-phase of the cell cycle. We have established in MB cells that Cdc14b and E2F6 are transcriptionally suppressed by the classical Hh pathway transcriptional suppressor, Gli3. Based on previous reports and our pilot experimental results, we propose that Hh signaling downregulates the expression of Cdc14b and E2F6 through Gli3, and promotes the progression of cell cycle from G1 to S phase, leading to the malignant proliferation of neural progenitor cells and the development of MB development. The present study aims to verify the aforementioned regulatory mechnism of Hh signaling to CDC14B and E2F6 in MB development, which will provide novel insights into the roles of Hh signaling and cell cycle inhibitor proteins in MB pathogenesis, and potentially provide new targets for treatment of Hh-driven MB.

髓母细胞瘤（MB）是儿童常见的颅内恶性肿瘤，Hedgehog（Hh）信号活化与MB发生相关，但其具体机制有待阐明。我们前期以Hh受体Smo转基因小鼠MB为模型，通过表达谱芯片筛选发现MB细胞中细胞周期抑制分子Cdc14b和转录因子E2F6表达发生明显下调。文献报道Cdc14b可通过结合p53上调细胞周期依赖性激酶抑制分子的表达，E2F6能够引起S期阻滞，从而阻止细胞从G1期向S期转化。我们发现Hh途径中转录抑制因子Gli3可结合于该两种分子的启动子区。结合文献报道和前期实验结果，我们提出MB中Hh信号通过Gli3下调Cdc14b和E2F6的表达，解除后者对细胞周期的抑制作用，促进细胞周期从G1期进入S期，导致细胞的恶性增殖及肿瘤的发生。本项目旨在验证Hh信号途径对上述细胞周期相关基因的调控作用，探讨其在MB发生中的作用，从而为深入理解MB的发生机制和鉴定MB新的候选治疗靶点提供理论依据。

髓母细胞瘤(MB)是一种严重的中枢神经系统恶性肿瘤，主要发生在儿童小脑。Sonic Hedgehog (Shh)信号通路的过度激活是Shh MB亚型发生发展的主要原因，其具体机制尚不清楚。在这项研究中，我们发现Shh通过非典型Hedgehog信号促进细胞增殖，其中Shh结合到Patched基因1上破坏了其与cyclin B1的相互作用，从而导致cyclin B1的核易位和细胞分裂相关基因的激活。此外，细胞周期蛋白B1在MB细胞中由于Cdc14b的解除和随后Cdc25c的激活而上调，Cdc25c是一种已知的维持细胞周期蛋白B1稳定性的磷酸酶。我们的研究结果表明，Cdc14b/cyclin B1在Hedgehog信号通路驱动的MB发病机制中的作用，这可能有助于确定MB治疗的候选治疗靶点。