N-cadherin胞内结构域对肿瘤干细胞特性的调控在神经内分泌前列腺癌发生中的作用

Neuroendocrine prostate cancer (NEPC) is an important issue which can emerge after the new generation of androgen-deprivation therapy. We know little of the mechanisms by which NEPC develops, and there is currently no effective treatment for NEPC. In previous studies, we have observed and demonstrated for the first time that N-cadherin was highly expressed in the nuclei of NEPC cells, which was caused by the nuclear translocation of N-cadherin intracellular domain after the cleavage. Meanwhile, our preliminary results showed the aberrant expression of ICD in nuclei could dramatically induce stem cell marker, but also contribute to the NEPC phenotype trans-differentiation. These findings implicated that N-cadherin ICD might involve in the etiology of NEPC by regulating cancer stem cell properties. Furthermore, we performed gene expression profiling analysis and found a panel of genes associated with β-catenin/TCF signaling pathway were upregulated in N-cadherin ICD-overexpression cells compared to control cells. In present application, we will further investigate the underlying mechanism of N-cadherin ICD in regulating cancer stem cell properties of NEPC, clarify the role of β-catenin/TCF signaling pathway in the pathogenesis, and evaluate the therapeutic potential of novel monoclonal antibody targeting the N-cadherin cleavage site in NEPC cells and orthotopic tumor mouse model. Our study will elucidate the etiology of NEPC and facilitate the clinical translation of new generated antibody, thus to provide a novel clinical strategy for NEPC treatment.

神经内分泌前列腺癌（NEPC）是新一代抗雄药物治疗后面临的重要课题，目前其发生机制尚不明确。前期研究中，我们首次发现并证实：N-cadherin在NEPC胞核内呈强阳性表达，其表达上调是由于N-cadherin剪切生成的胞内结构域（ICD）核转位导致。同时，ICD核内聚集可以导致干细胞标志物表达增加，并诱导NEPC表型的转化。通过基因表达谱分析，我们进一步发现在N-cadherin ICD过表达的细胞系中，β-catenin/TCF信号通路相关基因表达上调。本研究中，我们将深入研究N-cadherin ICD对肿瘤干细胞特性的调控在NEPC发生过程中的作用机制，揭示β-catenin/TCF通路是否介导了上述生物学过程，并探讨以N-cadherin剪切位点为靶点的新型抗体在NEPC中的治疗作用。本研究将为NEPC发生机制的阐明提供重要的理论基础，并有利于新型靶向抗体的临床转化。

神经内分泌前列腺癌（NEPC）是新一代抗雄药物治疗后面临的重要课题，目前其发生机制尚不明确。前期研究中，我们首次发现并证实：N-cadherin在NEPC胞核内呈强阳性表达，其表达上调是由于N-cadherin剪切生成的胞内结构域（ICD）核转位导致。同时，ICD核内聚集可以导致干细胞标志物表达增加，并诱导NEPC表型的转化。通过基因表达谱分析，我们进一步发现在N-cadherin ICD过表达的细胞系中，β-catenin/TCF信号通路相关基因表达上调。本研究中，我们首先在前列腺癌组织标本及细胞系中明确了N-cadherin ICD 对肿瘤干细胞特性及NEPC表型转化具有调控功能。此外，我们分别应用免疫荧光及免疫共沉淀技术明确了β-catenin/TCF信号通路介导了上述生物学过程。最后，在NEPC原位移植瘤小鼠模型中，初步探讨了以N-cadherin剪切位点为靶点的新型抗体2A9的治疗作用。我们的研究为NEPC发生机制的阐明提供重要的理论依据，并有利于新型靶向抗体的临床转化。