CCBE1介导肿瘤淋巴管生成调控非小细胞肺癌转移的作用及其机制

非小细胞肺癌（NSCLC）的转移是影响患者预后的重要因素，新生淋巴管的生成与NSCLC转移和预后不良密切相关。我们通过RNA-seq和生物信息学分析，发现胶原和钙结合EGF域１(CCBE1）在NSCLC转移组织中高表达，且在淋巴转移组中患者的预后与CCBE1的表达密切相关。此外，CCBE1促进NSCLC细胞的迁移和侵袭且诱导肿瘤淋巴管的生成，但对其在NSCLC转移中的作用机制缺乏进一步研究。免疫沉淀结果发现存在与CCBE1相互作用的蛋白，据此我们推测CCBE1与特异性蛋白结合，激活淋巴管生成相关信号通路，诱导肿瘤淋巴管生成进而促进NSCLC转移。因此本项目拟通过免疫共沉淀、质谱分析、抗体中和及共定位等方法，鉴定与其相互作用的蛋白，并从细胞学层面、自发淋巴转移小鼠模型、临床肿瘤标本等多方面阐明CCBE1诱导肿瘤淋巴管生成促进NSCLC转移的机制，为治疗NSCLC转移提供新靶点。

The metastasis of non-small cell lung cancer (NSCLC) is an important factor affecting the prognosis of the patients. The generation of new lymphatic vessels is closely related to NSCLC metastasis and poor prognosis. Our preliminary results showed that collagen and calcium binding EGF domain 1 (CCBE1) was highly expressed in NSCLC metastasis tissues by RNA-seq and the prognosis of patients with lymph node metastasis was closely related to the expression of CCBE1. In addition, CCBE1 promoted the migration and invasion of NSCLC cells and induced tumor lymphangiogenesis, but, the mechanism of CCBE1 in NSCLC metastasis is still elusive. We found that there was a protein interacting with CCBE1 through immunoprecipitation. Accordingly, we speculated that CCBE1 might interact with this specific protein ,thus activating lymphangiogenesis related signaling pathways, inducing lymphangiogenesis and promoting NSCLC metastasis. In this project, we intend to investigate the other potential protein interacting with CCBE1 by using a combination of methods including immunoprecipitation, mass spectrometry analysis, antibody neutralization and co-localization, and further investigate the mechanism of how CCBE1 is involved in tumor lymphangiogenesis and NSCLC metastasis from the cellular level, the spontaneous lymphatic metastasis model of mice, NSCLC samples and other aspects. Above all, our study might establish CCBE1 as a promising new target for NSCLC therapy.