Esrrb—Sox-5 正反馈调控环路在维持肺癌干细胞高侵袭表型中的作用机制研究

To elucidate the regulatory mechanisms of malignant phenotype of lung cancer stem cells (LCSCs) is the core prerequisite to understand the initiation and progression of lung cancer. Our preliminary studies showed that the LCSCs displayed highly invasive characteristics, the dialogue between Esrrb and Sox-5 was an important molecular event to maintain the highly invasive and metastatic potentials of LCSCs. However, the mechanism remains unclear. Further studies suggested that the expressions of Esrrb and Sox-5 are negatively correlated with prognosis in lung cancer, Esrrb can enhance the stability of β-catenin and regulate the expression of Sox-5 in a Wnt-independent manner, Sox-5 binding sites exist in the promoter region of Esrrb. The project proposed the hypothesis that the positive feedback regulation loop of Esrrb/β-catenin complex—Sox-5—Esrrb sustains the highly invasive potential of LCSCs. In this study, multiple molecular techniques including IP, GST pull-down, RNAi, ChIP and deletion mutation will be applied to decipher the mechanism that Esrrb promotes the nuclear translocation and the stability of β-catenin, and Esrrb/β-catenin complex regulates the expression of Sox-5 in LCSCs. We will also verify the molecular mechanism of Sox-5—Esrrb positive feedback regulation loop enhancing the β-catenin/TCF/LEF activities in a Wnt-independent manner. The project aims to reveal the molecular mechanisms of the invasion and metastasis of lung cancer from the dual perspective of understanding the tumor cell heterogeneity and mutual feedback regulation mode of stemness-related factors. This study will provide novel strategies for lung cancer diagnosis and treatment.

阐明肺癌干细胞（LCSCs）恶性表型的调控机制是理解肺癌发生与演进的“核心”条件。我们前期发现Esrrb与Sox-5“对话”是维持LCSCs高侵袭潜能的重要分子事件，但机制不清。新近研究提示Esrrb、Sox-5与肺癌预后负相关，Esrrb可增强β-catenin稳定性并以非依赖Wnt方式调控Sox-5，Esrrb启动子区存在Sox-5结合位点；故我们提出“Esrrb/β-catenin复合体—Sox-5—Esrrb正反馈环路维持LCSCs高侵袭表型”，拟采用IP、ChIP、RNAi、缺失突变技术明确Esrrb促进β-catenin核转位，形成Esrrb/β-catenin复合体并调控Sox-5；阐明Sox-5正反馈调控Esrrb以非依赖Wnt方式增强β-catenin/TCF/LEF活性。本研究从细胞异质性和“干性”因子互反馈调控双重角度揭示肺癌侵袭转移的机制，为探索肺癌诊疗提供新策略。

肺癌干细胞（Lung cancer stem cells, LCSCs）是肺癌发生、复发与转移的源动力，阐明肺癌干细胞（LCSCs）恶性表型的调控机制是理解肺癌发生与演进的“核心”条件。本研究发现LCSCs恶性表型调控机制存在复杂性和多样性的特征，SOX5、SOX2、ESRRB等多种“干性”因子形成的交互调控网络在维持LCSCs恶性表型中发挥重要作用，ESRRB可促进β-catenin的稳定核转位并被β-catenin招募而形成核内ESRRB/β-catenin转录激活复合物，调控下游核转录因子SOX5，SOX5又可反过来调控ESRRB的表达。SOX5正反馈调控ESRRB以非依赖Wnt方式增强β-catenin/TCF/LEF活性并转录激活SOX5以及EMT相关转录因子。此外，SOX5可通过与YAP1相互作用发挥促癌作用促进肺癌细胞侵袭和转移；阐明MPC1与STAT3相互作用抑制胞质STAT3活化并促进STAT3的线粒体转位，维持肺癌恶性表型。本项目探讨肺癌发生、发展以及高侵袭转移潜能的源头始动环节及其机制，研究结果对于阐明肿瘤发生机理以及探索更为有效地肺癌诊疗策略和改善患者预后具有重要的病理学和肿瘤学意义，并将为开发有效治疗肿瘤的药物提供新思路和潜在靶点。