M3乙酰胆碱受体组成型激活在非小细胞肺癌生长过程中的作用研究

项目名称： M3乙酰胆碱受体组成型激活在非小细胞肺癌生长过程中的作用研究

项目编号： No.81472187

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 魏晓莉

作者单位： 中国人民解放军军事科学院军事医学研究院

项目金额： 55万元

中文摘要： 近年研究发现乙酰胆碱具有生长因子样作用，能促进肿瘤发展进程。在众多的胆碱受体中，M3受体及其介导的信号通路居于更重要的地位。然而，迄今为止有关内源性乙酰胆碱及其受体系统影响肿瘤进程的方式和信号机制的深入研究报道较少。我们在前期研究中发现，采用药理学手段拮抗或敲减M3受体能显著抑制非小细胞肺癌的生长增殖，其机制涉及下调Cyclin D1-CDK4/6表达水平、抑制Rb磷酸化，以及诱导G0/G1期阻滞；拮抗M3受体还可下调Akt磷酸化水平，及上调JNK磷酸化。本项目将在前期研究基础上，研究并证实非小细胞肺癌中M3受体的组成型激活，及其参与调控肿瘤细胞生长、增殖、凋亡和迁移的可能方式，为确立非神经元胆碱能系统在肿瘤生长调控中的地位，以及未来可能的NSCLC组合化疗策略选择提供依据。

中文关键词： 非小细胞肺癌；非神经元胆碱能系统；M3乙酰胆碱受体

英文摘要： Acetylcholine (Ach) was found to have growth factor-like effect, and could promote the progression of tumor. Among the Ach receptor family members, M3 receptor and its signal transduction were proved to be more important during this process. To date, there are fewer studies on the possible manner and signal pathway through which Ach and its receptor system affect tumor progression. In our previous studies, we have found that pharmacological antagonizing and knock-down of M3 receptor significantly inhibited the proliferation of non-small cell lung cancer (NSCLC) cells, the mechanism was related to induction of G0/G1 phase arrest through downregulation of Cyclin D1-CDK4/6 and decreasing of Rb phosphorylation. Antagonizing M3 receptor also resulted in downregulation of Akt phosphorylation and upregulation of JNK phosphorylation. Based on these results, we will investigate and validate the constitutive activation of M3 receptor and potential mechanisms underlying the involvement of M3 receptor in NSCLC cellular growth, proliferation,apoptosis and migration. This study is to provide evidence for ascertaining the role of non-neuronal cholinergic system in the tumor growth process and assigning an alternative of combination strategy for NSCLC therapy in the future.

英文关键词： NSCLC;non-neuronal cholinergic system;M3 acetylcholine receptor