非小细胞肺癌（NSCLC）发病率日趋增加。MAPK相互作用激酶（Mnk）和依赖其磷酸化的真核细胞翻译起始因子-4E（eIF4E）的激活在肿瘤进展中起重要作用。我们前期发现Mnk抑制剂逆转RAD001治疗NSCLC诱导的eIF4E磷酸化和Akt活化；增加E-cad、下调Vim表达，抑制β-catenin核转位，抑制细胞增殖，诱导凋亡。据此提出如下科学假说：Mnk-eIF4E/β-catenin轴的激活导致NSCLC进展；靶向抑制Mnk-eIF4E/β-catenin轴，可能经Akt依赖方式调控NSCLC细胞内β-catenin的分布及其下游基因的表达，逆转上皮间质转化，诱导凋亡，抑制细胞增殖、侵袭和转移。拟从临床肺癌标本、细胞和动物模型三个层面阐明这一假说的具体机制。本项目的实施为基于靶向抑制Mnk-eIF4E/β-catenin轴治疗NSCLC提供实验依据，具有重要理论意义和临床应用价值。

The incidence rate of non-small cell lung cancer (NSCLC) has the most rapidly increasing in the people of our city. Activation of the MAP kinase-interacting kinases (Mnk) and phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) catalyzed by Mnk play vital roles in tumor progression. In our preliminary experiment, we found that Mnk inhibitor CGP57380 reversed RAD001-induced eIF4E phosphorylation and inhibited the Akt activation in the NSCLC cell lines in vitro and in vivo. Our results also showed that CGP57380 increased expression of E-cadherin, decreased Vimentin expression and inhibited the nuclear translocation of β-catenin protein in the NSCLC cell lines. Furthermore, Mnk inhibitor suppressed cell proliferation and induced cell apoptosis of NSCLC cells. Basing on the results above, we put forward the hypothesis that the activation of Mnk-eIF4E/β-catenin axis promotes the NSCLC progression; targeted inhibition of Mnk-eIF4E/β-catenin axis could regulate the distribution of β-catenin protein and expressions of its downstream genes via Akt-dependent manner, abrogate epithelial-mesenchymal transition, and inhibit the cell proliferation, aggression and metastasis of NSCLC through inducing cell apoptosis. In the project, we will plan to confirm the scientific hypothesis and investigate its specific molecular mechanisms through a series of combination experiments with four factors and three levels from the clinical specimens of human non-small cell lung cancer, cell lines and animal models. The completion of this project will lay the profound experimental foundations for targeted treatment basing on Mnk-eIF4E/β-catenin axis in NSCLC, which is of both significances on theoretical and clinical therapy.