肺癌候选抑癌基因RBM5在吸烟相关肺癌中的作用及分子调控机制

Lung cancer ranks among the most common and lethal malignancies worldwide according to the World Health Organization. Cigarette smoking is the most common single cause for developing lung cancers. Accumulated evidence suggested that lung cancer in ever smokers and never smokers follow distinct molecular pathways and may therefore respond to distinct therapy. A fundamental issue for elucidating lung carcinogenesis is how cigarette smoking interacts with genes that are related to this process. RBM5 is a new candidate tumor suppressor gene in lung cancer, and Wnt/beta-catenin signaling pathway is involved in lung cancer associated with cigarette smoking. Our study showed that the expression level of RBM5 was lower in lung cancer tissues of never smoker than in lung cancer tissues of smokers; exogenous RBM5 can downregulate beta-catenin(the key gene of Wnt/beta-catenin pathway). Additional studies will be essential to re-evaluate the individual risk of developing lung cancer and to assess its prevention based on the RBM5 alterations. We will use plasmid transfection, RNAi, luciferase reporter gene assay, PCR-array et al in human cell lines, animal models and human lung cancer tissues. We will reveal the expression of RBM5 and its splice variants during the development of lung cancer under the status of ever smoke and never smoke; their modulation on the inhibition/activation of Wnt/beta-catenin pathway and target genes. This study will demostrate that the role of RBM5 gene and its splice variants in lung carcinogenesis of never smoke and ever smoke and their regulation on Wnt/beta-catenin signal pathway. Our study will provide a scientific basis for early warning of high risk, early diagnosis and gene targeted intervention research in lung cancer.

肺癌仍是全球发病率、死亡率最高的恶性肿瘤，吸烟是肺癌首要的危险因素。RBM5是新的肺癌候选抑癌基因，Wnt/β-catenin信号通路与吸烟相关的肺癌关系密切。我们的前期研究发现，RBM5在吸烟者与非吸烟者肺癌组织的表达存在明显差异；导入外源性RBM5时可下调β-catenin（Wnt/β-catenin信号通路的关键基因）的表达水平。本研究将进一步①在人细胞系、动物模型以及人肺癌组织三个层面，采用转染、RNAi、荧光素酶报告基因检测、PCR-array等方法，研究吸烟、非吸烟、戒烟状态下肺癌发生、发展过程中，RBM5和其剪接变异体表达的变化；②探讨其与Wnt/β-catenin信号通路抑制/激活的关系及其作用靶点。明确RBM5基因及不同剪接变异体在非吸烟和吸烟相关肺癌变中的作用及对Wnt/β-catenin信号通路的调控作用，为肺癌高危人群预警、早期诊治特别是靶向干预研究提供科学依据。

肺癌仍是全球发病率、死亡率最高的恶性肿瘤，吸烟是肺癌首要的危险因素。RBM5 是新的肺癌候选抑癌基因，它最重要的特征是参与调控细胞促凋亡过程，而且与肿瘤的发生密切相关。RBM5 在吸烟相关肺癌的发生和发展中的作用机制仍不明确；尚需进一步研究RBM5 与吸烟相关的信号通路之间的关系，以阐明 RBM5 的在吸烟相关肺癌中的功能及分子机制，Wnt/β-catenin 信号通路与吸烟相关的肺癌关系密切。本研究将①在人气管上皮细胞，采用MTT、RT-PCR、Western blot、转染、荧光素酶报告基因检测等方法，研究吸烟状态下肺癌发展过程中，RBM5的变化，首次在细胞水平明确了RBM5在香烟提取物（CSE）作用后表达明显降低；②明确香烟提取物（CSE）可以异常激活 Wnt/β-catenin 信号通路。③发现了RBM5 基因对Wnt/β-catenin 信号通路的调控作用。RBM5作为β-catenin的上游基因，在吸烟相关肺癌变中调控 Wnt/β-catenin信号通路，为肺癌高危人群预警、早期诊治特别是靶向干预研究提供科学依据。