新肺癌基因mdig对细胞周期基因的调控机制探讨

项目名称： 新肺癌基因mdig对细胞周期基因的调控机制探讨

项目编号： No.81472194

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： 赵洪文

作者单位： 中国医科大学

项目金额： 78万元

中文摘要： 肺癌居肿瘤发病之首，死亡率高。矿物粉尘诱导基因(Mineral Dust Induced Gene；mdig)是2005年在矿工肺泡巨噬细胞中发现的一种新肺癌基因，有促细胞增殖作用，主要在细胞周期的G1期向S期转换上。但mdig与细胞周期基因的关系尚无研究。肿瘤的发生与细胞周期调控失常导致细胞增殖失控有关。因此，本项目将从体外和体内来探讨mdig对细胞周期基因的调控机制。在体外实验部分：首先应用RNAi和过表达技术筛选出mdig相关的目标细胞周期基因，并确定是mdig的下游靶基因；应用基因敲除、siRNA、过度表达和染色质免疫共沉淀等技术探讨 mdig对细胞周期基因和细胞周期进程的调控机制。然后，采用显微注射法制备肺组织特异表达mdig的转基因小鼠模型，探讨mdig在体内对肺癌发生的影响及其与细胞周期基因的关系。本研究为将来对肺癌，乃至其他肿瘤的靶向治疗提供理论依据。国内外未见类似报道。

中文关键词： 肺癌；矿物粉尘诱导基因；细胞周期；癌基因；转基因小鼠

英文摘要： Lung cancer, the most common cancer worldwide, is the top leading cause of cancer-related death because of its unclear pathogenesis and no effective treatment. Mineral dust-induced gene (mdig) is a novel lung cancer-associated oncogene identified in alveolar macrophages of coal miners in 2005, playing a role in cell proliferation,especially in the cell cycle G1-S transition. But its relationship with cell cycle-related gene is still unclear. It has long been established that tumorigenesis is largely resulted from genetic abnormalities, including abnormal regulation of cell cycle resulting in uncontrolled cell growth or proliferation. In the present proposal, the mdig-related target cell cycle genes will be firstly investigated in vitro by the use of gain-of-function (overexpression) and loss-of-function (siRNA-mediated RNA interference) strategies, and then further identified as downstream target gene of mdig. The regulatoty mechanism of mdig on its downstream cell cycle gene and cell cycle progression will be explored by applying molecular biological techniques including gene knochout, siRNA, overexpression and co-immunoprecipitation. On the basis of above study, the transgenic mouse model of specific expression mdig in lung will be established by microinjection to futher clarify the role of the mdig, in vivo, in lung cancer pathogenesis and the regulation of cell cycle genes. The results obtained from this study will be helpful in targeted therapy for lung cancer and even other neoplasms . There is no similar report worldwide up to now.

英文关键词： lung cancer;mineral dust induced gene;cell cycle;oncogene;transgenic mouse