FGFR2与NOK相互作用调控GSK-3β/Snail信号通路介导肺鳞癌EMT的机制研究

Molecular targeted therapy is an important method for the treatment of lung cancer. However, it is difficult for patients with squamous cell lung carcinoma to benefit from the existing therapeutic targets, and the progress of treatment is lagging behind. So the pathogenesis and therapeutic targets for squamous cell lung carcinoma need to be further studied. The applicant found that NOK as an oncogene was an independent prognostic factor of patients with squamous cell lung carcinoma, could promote the metastasis of squamous cell lung carcinoma and regulate GSK-3β/Snail which is the key signaling pathway in epithelial mesenchymal transition (EMT). NOK is expected to become a new therapeutic target, but its activation mechanism in squamous cell lung carcinoma is unclear. Previous studies found that the expression of NOK and FGFR2 in squamous cell lung carcinoma were correlated and co-localized. Co-IP showed NOK and FGFR2 could form protein complexes. Therefore, we hypothesize that FGFR2 and NOK interact with each other in squamous cell lung carcinoma, and promote EMT by regulating GSK-3β/Snail signaling pathway. The purpose of this study in vivo and in intro is to confirm the role of FGFR2, NOK and GSK-3β/Snail signaling pathway in EMT of squamous cell lung carcinoma, to explore the relationship and interaction mechanism between FGFR2 and NOK, to find the influence of the interaction to GSK-3β/Snail signaling pathway. This study may provide new ideas for the targeted therapy of squamous cell lung carcinoma.

分子靶向治疗是目前肺癌治疗的重要手段，但是肺鳞癌患者却难以从现有的靶点获益，治疗进展滞后，其发病机制及治疗靶点亟待深入研究。课题组研究发现癌基因NOK影响肺鳞癌患者预后，促进肺鳞癌转移，且对上皮间质转化（EMT）中的关键信号通路GSK-3β/Snail具有调控作用，有望成为新的治疗靶点。然而，NOK在肺鳞癌细胞中的活化途径尚不清楚。前期研究发现NOK和FGFR2在肺鳞癌中的表达具有相关性，且存在共定位现象，免疫共沉淀显示两者能够形成蛋白复合物，由此我们提出假设：FGFR2与NOK在肺鳞癌细胞中发生相互作用，通过调控GSK-3β/Snail信号通路，促进肺鳞癌EMT。本课题拟通过体内及体外实验证实FGFR2、NOK及GSK-3β/Snail信号通路在肺鳞癌EMT中的作用，探索FGFR2/NOK的相互作用关系、作用机制及对GSK-3β/Snail信号通路的影响，为肺鳞癌的靶向治疗提供新的思路。

STYK1（又称NOK）作为一种蛋白酪氨酸激酶，在多种肿瘤发病中发挥重要作用，但是其在肺鳞癌发病中的作用及相关机制尚有待深入研究。本课题围绕“FGFR2与NOK相互作用调控GSK-3β/Snail信号通路介导肺鳞癌的上皮间质转化（EMT）”这一科学假说，开展了临床、体内及体外等多个水平的研究：（1）通过对361例肺癌患者的肿瘤样本检测及临床资料收集，发现FGFR2和STYK1在肺鳞癌及肺腺癌中均存在特异性的高表达，对肺癌患者的预后具有显著影响，两者的表达水平具有相关性，ROC分析证实两者的基因表达水平具有潜在的诊断价值；（2）细胞功能学实验和体内成瘤实验证实FGFR2和STYK1均能够影响肺鳞癌细胞的增殖、凋亡及转移、侵袭；（3）临床研究发现肿瘤组织中STYK1的表达水平和GSK-3β的磷酸化水平呈正相关，体外实验证实STYK1的高表达能够促进GSK-3β的磷酸化，影响EMT标志物的表达水平，而改变FGFR2的表达水平则能够调控这一过程。这些研究结果进一步证实了FGFR2和STYK1在肺鳞癌发病中的重要作用，也初步揭示了两者参与肺鳞癌发病的作用机制。在此基础上，我们还利用FGFR2在肺及肺癌组织中的表达特点，开展了纳米药物载体、分子印迹等靶向治疗技术的探索性研究。