E3泛素连接酶Smurf1通过泛素化PTEN对胶质母细胞瘤调控网络的研究

Glioblastoma (GBM) is a highly malignant brain tumor. PI3K/Akt/mTOR pathway is highly elevated in up to 90% of GBM cells. However, rapamycin, as a PI3K/Akt/mTOR pathway-targeted inhibitor, was strikingly resistant in the treatment of GBM. PTEN is the sole central negative regulator of PI3K signaling. However, PTEN mutation or deletion accounts for 5%-40% or 60%-80% of GBM cells respectively. Loss of PTEN leads to constitutive activation of the PI3K/Akt/mTOR signal transduction pathway and has been associated with resistance to mono-rapamycin treatment. This study is to investigate how PTEN is regulated in GBM cells. We analyzed TCGA database and found that elevated E3 ubiquitin ligase Smurf1 expression correlated with a worse outcome in GBM patients. In our previous experiments, we found that Smurf1 expression was increased in GBM patients and different cell lines. A mechanistic study shows that Smurf1 promotes PI3K/Akt/mTOR activation. In addition, PTEN was regulated by ubiquitylation and degradation through interacting with Smurf1. In this study we will use cell and animal models to further explore the mechanism of Smurf1 in rapamycin resistance and identify the regulatory network. This will be helpful for further understanding the molecular mechanism underlying GBM and could lead to novel therapeutic interventions of GBM.

胶质母细胞瘤（GBM）是一种高度恶性的原发性脑肿瘤，约90%的GBM细胞中PI3K/Akt/mTOR信号通路高度激活，然而该通路的抑制剂雷帕霉素在治疗GBM的过程中却具有很强的耐药性。PTEN是此通路中唯一负调控因子，在GBM细胞中却发生突变（5%-40%）或缺失（60%-80%），其功能丧失与雷帕霉素耐药性相关。本课题为了研究PTEN在GBM细胞中如何被调控，TCGA数据库分析表明GBM患者中E3泛素连接酶Smurf1高表达，与预后不良成正相关。前期研究验证了Smurf1在GBM病人与细胞系中高表达；机制方面发现Smurf1增强PI3K/Akt/mTOR通路，泛素化并降解PTEN。本课题根据我们的前期发现，在细胞和动物模型中探索Smurf1调控雷帕霉素耐药性的机制以及其调控网络。本研究有助于进一步了解GBM的发病机理，通过对Smurf1的机制研究寻找治疗GBM的新方法。

胶质母细胞瘤（GBM）是一种高度恶性的原发性脑肿瘤，约90%的GBM细胞中PI3K/Akt/mTOR信号通路高度激活，然而该通路的抑制剂雷帕霉素在治疗GBM的过程中却具有很强的耐药性。PTEN是此通路中唯一负调控因子，在GBM细胞中却发生突变（5%-40%）或缺失（60%-80%），其功能丧失与雷帕霉素耐药性相关。本课题为了研究PTEN在GBM细胞中如何被调控，TCGA数据库分析表明GBM患者中E3泛素连接酶Smurf1高表达，与预后不良成正相关。本课题研究验证了Smurf1在GBM病人与细胞系中高表达；机制方面发现Smurf1增强PI3K/Akt/mTOR通路，泛素化并降解PTEN。并在细胞和动物模型中研究Smurf1调控雷帕霉素耐药性的机制以及其调控网络。本研究有助于进一步了解GBM的发病机理，通过对Smurf1的机制研究寻找治疗GBM的新方法。