SMC4及其肺发育相互作用分子在肺癌发生发展中的作用研究

Tumor is a kind of complicated molecule network disease, with the direct research on its molecular network being very difficult. It is suggested to take advantage of the similarity between ontogenesis and carcinogenesis, and to grasp the molecular network of the tumor by means of the gene interaction patterns in the context of development. In the preliminary work, SMC4 was found to be important in the process of human lung development, potential interaction molecules (SMC2, UBE2C, and PTTG1) of SMC4 in the process of development were predicted, and the molecular network was constructed. Preliminary experiments proved that SMC4 has an effect on lung carcinogenesis and progression. The present research is directed to explore the effect of SMC4 in the process of lung carcinogenesis and progression, to determine the interaction molecules of SMC4 in development, and to verify if SMC4 still function through them in the process of lung carcinogenesis and progression.

肿瘤是一种复杂的分子网络病，直接研究它的分子网络难度巨大。我们提出利用胚胎发育与肿瘤发生发展的相似性，借助胚胎发育基因相互作用模式认识肿瘤的分子网络。前期我们发现了SMC4基因在人胚胎肺发育过程中有重要地位，预测了SMC4基因在发育过程中潜在的相互作用分子（SMC2、UBE2C和PTTG1），并构建了分子网络。初步实验证明SMC4基因对肺癌发生发展有作用。本研究拟探索SMC4基因在肺癌发生发展过程中的作用，确定SMC4在发育中相互作用分子，验证在肺癌发生发展过程中SMC4是否仍旧通过它们继续发挥功能。

肿瘤是一种复杂的分子网络病，直接研究它的分子网络难度巨大。我们提出利用胚胎发育与肿瘤发生发展的相似性，借助胚胎发育基因相互作用模式认识肿瘤的分子网络。前期我们基于44例人胚胎肺发育样本基因表达谱数据和STRING数据库，构建了蛋白相互作用网络，发现其中一个包含SMC4在内共18个基因的核心模块与染色质组装和RNA剪切密切相关。免疫组化结果表明，SMC4在肺腺癌组织中较癌旁正常肺组织中表达水平升高，与肺腺癌患者不良预后显著相关。细胞学研究证实降低SMC4表达水平，能够显著抑制肺腺癌细胞系A549的增殖和侵袭能力。免疫共沉淀联合质谱分析发现，在人支气管上皮永生化细胞系MBE细胞中，染色体集缩蛋白通过SMC4与DDX46（DEAD (Asp-Glu-Ala-Asp) box polypeptide 46）蛋白有相互作用，后续采用Co-IP结合Western blot，证实SMC4在MBE和肺腺癌细胞系A549中均与DDX46基因具有相互作用。而DDX46是参与mRNA剪切的重要基因。综上，我们通过对人胚胎发育相关基因表达网络的挖掘发现了与人肺癌发生发展密切相关的SMC4基因，并且发现SMC4可能是通过与DDX46相互作用而引起细胞内mRNA前体剪切加工出现障碍进而影响肿瘤细胞的恶性表型。