Cul4A诱导肺癌发生发展的作用机制的研究

Lung cancer is the most frequent cancer in the world.Since its mechanism remains poorly understood,it is very important to study the mechanisms causing lung cancer.We previously demonstrated the amplification of Cul4A copy number and the increased expression of Cul4A protein in malignant pleural mesothelioma cells.To explore the mechanisms of lung cancer occurring and progressing,we have developed a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumor. We hypothesize that Cul4A play an important role on the initiation and progressing of lung cancer.To test our hypothesis,1)We will validate that overexpression of Cul4A promotes lung tumor cell growth in the transgenic mouse model by siRNR,Semi-Quantitative RT-PCR,and immunohistochemical analysis,suggesting that Cul4A regulates their substrates expression in tumor development;2)We will prove that progressive genomic instability happens in the transgenic mouse lung tumors that was further validated by the results from pericentrin and CDT1 protein expression and array Comparative Genomic Hybridization analysis；3)Cul4A knock down and the chemotherapy drug cisplatin will show a synergistic effect in inhibiting human lung cancer cells.From these findings, we will conclude that Cul4A plays an important role in tumor development in this mouse model.A better understanding of Cul4A signaling pathways and mechanisms in the growth of lung tumors in this mouse model could provide new insights into the development of new approaches for diagnosis and prognosis of lung cancer,and could leade to targeted therapies for lung cancer.

本项目为致力于解决肺癌这一全球所面临的重大科学问题而设立。肺癌是目前对人类威胁最大的恶性肿瘤，然而关于肺癌发生的分子机制依然不清楚。我们前期的研究证实Cul4A是恶性胸膜间皮瘤的癌基因，而Cul4A在肺癌发生中的作用却鲜有报导。为阐明肺癌发生发展的分子机制，课题组已通过Cre-LoxP重组系统建立了Cul4A转基因小鼠肺腺癌模型。本项目拟在此肺癌模型基础上，结合人类肺癌细胞系，利用siRNA、半定量RT-PCR、荧光原位杂交、矩阵比较基因组杂交和免疫组织化学技术，针对Cul4A过表达对细胞周期蛋白抑制因子和基因组稳定性的影响，探讨了肺癌的发生发展机制。这些研究结果无疑对探讨人类肺癌的发生机理及其预防提供了良好的实验材料，从而为人类肺癌的早期诊断、疾病监测、判断预后和开发新的肺癌靶向治疗药物提供强有力的科学依据。

肺癌是目前对人类威胁最大的恶性肿瘤，然而关于肺癌发生的分子机制依然不清楚。我们前期的研究证实Cul4A是恶性胸膜间皮瘤的癌基因，而Cul4A在肺癌发生中的作用却鲜有报导。为阐明肺癌发生发展的分子机制，课题组已通过Cre-LoxP重组系统建立了Cul4A转基因小鼠肺腺癌模型。本项目拟在此肺癌模型基础上，结合人类肺癌细胞系，利用siRNA、半定量RT-PCR、荧光原位杂交、矩阵比较基因组杂交和免疫组织化学技术，针对Cul4A过表达对细胞周期蛋白抑制因子和基因组稳定性的影响，探讨了肺癌的发生发展机制。这些研究结果无疑对探讨人类肺癌的发生机理及其预防提供了良好的实验材料，从而为人类肺癌的早期诊断、疾病监测、判断预后和开发新的肺癌靶向治疗药物提供强有力的科学依据。