Trim32通过对细胞分裂模式的调控抑制小脑髓母细胞瘤发生发展的机制研究

Medulloblastoma is the most common pediatric malignant tumor. The biological process underlying the tumorigenesis of medulloblastoma is unclear. We found that cell division mode change mediates the regulation of cerebellar granule neurogenesis controlled by the Sonic Hedgehog (Shh) signaling during cerebellar development using wild type and Patched+/- transgenic mice. The result was published in Stem Cell Report in 2015. Patched+/- (Pth+/-) transgenic mice, in which SHH signaling is activated, is also a medulloblastoma model. In the current study, we focus on the effect of Trim32 in cerebellar cell division modes and medulloblastoma. We have obtained preliminary results indicating that 1) Trim32 is asymmetrically distributed during cell divisions of cerebellar granule cell progenitors; 2) Trim32 is downregulated in cerebellar granule cell progenitors and medulloblastoma; 3) Trim32 knockout increases the incidence of medulloblastoma in Patched+/- mice; 4) Symmetrical and asymmetrical stem cell divisions exist in medulloblastoma; 5) Upstream and downstream mechanisms including: BMP2 transcriptionally induces Trim32 expression by smad1/5; Trim32 immunoprecipitates Gli1; Trim32 downregulates its interacting protein Prl1 and oncogene Myc. Brat, the homolog of Trim32 in Drosophila, was indicated as a potential tumor suppressor. The action of Trim32 in mammalian cancer is still not quite clear. Based on our published paper and preliminary data, we will investigate whether and how Trim32 inhibit the tumorigenesis of medulloblastoma via modulation of cell division modes in the cerebellum. This study will provide us new insight into the mechanism of cerebellar tumorigenesis from a new angle of Trim32 modulation and tumor stem cell division mode change and likely to provide a novel therapeutic strategy in the future.

髓母细胞瘤是中枢神经系统恶性程度最高的肿瘤之一，其机理尚不清楚。我们前期论文表明，小脑颗粒前体细胞分裂模式介导Shh信号通路调控的小脑发育过程以及髓母细胞瘤发生早期。我们预实验发现①Trim32在小脑颗粒前体细胞分裂中呈不对称分布。②Trim32 在颗粒前体细胞和髓母细胞瘤中表达下降。③敲除Trim32 后，Patched+/-小鼠更容易发生髓母细胞瘤。④髓母细胞瘤存在肿瘤干细胞对称和不对称分裂。⑤可能的上下游机制：BMP2通过smad1/5 复合物上调Trim32表达；Trim32免疫沉淀Gli1；Trim32下调其互作蛋白Prl1和Myc的表达。Trim32作为抑癌基因的研究多集中于果蝇等低等动物，在哺乳类刚起步，尚未完全阐明。基于前期研究和预实验，我们将探索Trim32介导的特异信号通路和细胞分裂模式的调控及其对髓母细胞瘤的作用，从一个新角度阐明肿瘤发生机理，为临床提供新思路和靶标。

髓母细胞瘤是中枢神经系统恶性程度最高的肿瘤之一，其机理尚不清楚。我们前期论文表明，小脑颗粒前体细胞分裂模式介导Sonic hedgehog（SHH）信号通路调控的小脑发育过程以及髓母细胞瘤发生早期。SHH信号转导是维持小脑发育过程中颗粒神经元前体细胞（GNPs）自我更新的重要信号，其失调导致了肿瘤的发生。然而，SHH信号在小脑发育过程中是如何被控制的，目前还不清楚。本研究中，我们发现了细胞命运决定因子Trim32在有丝分裂的GNPs的细胞质中呈不对称分布，Trim32基因敲除使GNPs处于增殖和未分化状态。此外，Trim32基因敲除可增加Ptch1突变小鼠髓母细胞瘤的发生率。机制上，Trim32通过其NHL结构域与Gli1结合，Gli1是SHH信号转导通路的关键因子。Trim32通过其NHL结构域降解Gli1，从而对抗SHH通路。这些发现提供了一个新的机制，即Trim32可能是一个重要的细胞命运调节因子，通过拮抗SHH信号促进GNPs的分化，并在髓母细胞瘤的形成中起到肿瘤抑制作用。本研究发表在Cell Death and Differentiation上（2020，IF10.717）。Trim32介导的特异信号通路和细胞分裂模式的调控及其对髓母细胞瘤的作用，将从一个新角度阐明肿瘤发生机理，为临床提供新思路和靶标。