研究表明抑癌基因LKB1可以抑制肺癌转移，具体机制有待深入探索。我们发现在LKB1缺失的癌细胞株中，胞外分泌复合体重要成员Exo70发生N-连接糖基化，此糖基化促进肺癌细胞转移，回补LKB1能够抑制Exo70糖基化，提示LKB1可能通过调控Exo70糖基化抑制肺癌细胞转移。本项目将首先在细胞和动物水平，运用点突变、糖基化修饰、RNA干扰、3D球体细胞侵袭分析等方法研究：1. Exo70 糖基化对胞外分泌复合体装配及细胞运动和迁移的影响；2. LKB1调控Exo70糖基化的分子机制，包括磷酸化以及糖基转移酶调控；3. LKB1调控Exo70糖基化如何影响肺癌细胞转移。进而在临床样本中分析LKB1缺失与Exo70 糖基化的相关性以及Exo70糖基化与肺癌病理分期以及生存预后的相关性。最后以Exo70糖基化为靶点筛选抗肺癌先导化合物。项目将为肺癌的诊断、靶向治疗以及相关靶点药物开发提供理论依据。

Tumor suppressor LKB1 can inhibit the metastasis of lung cancer. However, the exact mechanisms remain elusive. Our preliminary results showed that in those cancer cell lines, in which LKB1 was absent, exo70, an important member of the exocyst, is N-linked glycosylated. Further studies indicated that the glycosylation leads to the migration of lung cancer cells, and the glycosylation could be inhibited by LKB1,which indicated that LKB1 might inhibit the lung cancer cell migration via regulation of Exo70 glycosylation. In this project, firstly, in cell and animal models, by using point mutations, glycosylation modifications, RNA interferences and 3D cell invasion assay, we will study: 1) the roles of Exo70 glycosylation in exocyst assembly and cell movement and migration; 2) the molecular mechanisms involved in LKB1 regulated exo70 glycosylation, including phosphorylation and glycosylation enzymes regulation; 3) mechanisms involved in LKB1 regulated exo70 glycosylation and lung cancer cell migration. Then, we will study the relationship between LKB1 and exo70 glycosylation as well as exo70 glycosylation and patient pathological staging and prognosis in patient tissue samples. Based on the above study, we will screen the lead compounds targeting the exo70 glycosylation to inhibit lung cancer cell migration. This study will provide theoretical basis for the diagnosis, target therapy and related drug discovery of lung cancer.