LKB1信号通路对细胞周期和细胞极性的协同调控机制研究

项目名称： LKB1信号通路对细胞周期和细胞极性的协同调控机制研究

项目编号： No.81201544

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 梁小燕

作者单位： 重庆医科大学

项目金额： 23万元

中文摘要： 增殖失控和极性紊乱是上皮细胞恶性肿瘤的两大特征，虽然近年来相关研究取得不少进展，但其信号转导机制仍不十分明确，特别是二者在肿瘤发生中的交互作用更知之甚少。抑癌基因LKB1在细胞增殖和极性调控中发挥着重要作用。我们前期研究发现，抑制正常细胞LKB1表达，p53和p16下调，细胞周期进程加快；恢复Hela细胞LKB1表达，细胞生长减慢，体积变小，形态变梭形，提示LKB1调控细胞周期和细胞极性的信号通路紧密联系、协同作用，共同决定细胞的转归。本课题拟采用分子生物学技术，建立LKB1基因表达沉默的人上皮细胞实验模型与LKB1基因表达恢复的人癌细胞实验模型，结合体外三维细胞培养技术，从细胞水平和分子水平研究LKB1基因对细胞周期和细胞极性的调控机制，解析两大通路间的协同作用和交联对话，以进一步揭示肿瘤发生的分子信号网络，为肿瘤防治提供新思路和理论依据。

中文关键词： 细胞周期；细胞极性；LKB1；MARK；AMPK

英文摘要： Cancer can develop in virtually any of the body's tissues, and the basic processes that produce cancer are quite similar in all forms of the disease. Loss of growth control and disruption of epithelial polarity are two hallmarks of cancer cells. After years of extensive scientific discovery, valuable information has been learned about the networks regulating cell growth and cell polarity, but the underlying molecular mechanisms, especially the crosstalk between them, are still elusive. LKB1 is a critical tumor suppressor, which regulates numerous biological pathways including apoptosis, cell proliferation, epithelial polarity, cell migration, and so on. In our previous study we have shown that endogenous LKB1 knockdown in two normal cell lines accelerates cell cycle progression through G1/S checkpoint by inhibition of p53 and p16 pathways. In addition, we have found reintroduction of LKB1 into LKB1 deficient Hela cells inhibited cell growth significantly and changed Hela cells into small, spindle-shaped cells, suggesting LKB1 may coordinate the cell growth and cell polarity pathways. In the present study, with molecular techniques, we ablate endogenous LKB1 expression in human normal epithelial cells and express exogenous LKB1 protein in human cancer cells. Based on the three-dimensional cell-culture models, we

英文关键词： Cell cycle；cell polarity；LKB1；MARK；AMPK