DNMT3b/miR-203/DNA-PKcs新信号通路调节喉癌放疗敏感性的机制研究

项目名称： DNMT3b/miR-203/DNA-PKcs新信号通路调节喉癌放疗敏感性的机制研究

项目编号： No.81202138

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2

项目作者： 卞卡

作者单位： 中国人民解放军第四军医大学

项目金额： 23万元

中文摘要： 放疗是喉癌除手术疗法外的主要治疗手段，探讨放疗敏感性调节机制对于提高治疗效果至关重要。在前期工作中，我们分析了miR-203在喉癌细胞中可能的生物学功能，发现它可以结合DNA损伤修复功能分子（DNA-PKcs）的3'UTR抑制其表达，而DNA-PKcs的过度活化正是导致放疗抵抗的重要原因，这提示miR-203有可能通过阻断DNA-PKcs功能提高放疗敏感性。同时，miR-203在多种肿瘤中因启动子甲基化而呈现低表达，我们发现甲基转移酶DNMT3b与miR-203之间存在相互负向调控环路。因此，我们提出DNMT3b/miR-203/DNA-PKcs这一新信号通路的假想。拟在此前提下，利用体内外生物学实验分析miR-203在喉癌放疗敏感性调节中的作用，明确该信号通路是否存在于放疗抵抗的临床患者体内。该研究对于分析临床患者对放疗敏感性的差异，深入理解放疗敏感性的调控机制和指导临床治疗具有重要意义

中文关键词： 微小RNA；放疗敏感性；DNA损伤修复；细胞生长；细胞迁移

英文摘要： Radiotherapy is the primary treatment for laryngeal carcinoma besides surgery. As some patients are highly resistant to radiotherapy, exploring the regulatory mechanisms of radiation sensitivity is essential for improving the therapeutic effect.In previous works, we found very low expression of miR-203 in laryngeal cancer cells compared with normal cells, but, that miR-203 can inhibit the expression of DNA-PKcs by direct binding. It has been suggested that the excessive activation of DNA-PKcs is an important reason leading to radiation resistance, which implies that low expression of miR-203 may relate to the radiation resistance induced by over-expression of DNA-PKcs. Also, on the one hand, miR-203 shows a low expression state in a variety of tumors by promoter methylation, on the other hand, bioinformatics prediction results show that DNMT3b methyltransferase is likely to be another down-stream regulator of miR-203. Therefore, we postulate that DNMT3b/miR-203/DNA-PKcs signaling pathway may involve in the radiation resistance of some cancer patients. We will analyze miR-203 regulatory mechanisms of radiation sensitivity in laryngeal carcinoma, and mainly clear whether this new signaling pathway DNMT3b/miR-203/DNA-PKcs exists in the cancer patients with radiation resistance. Full understanding of the biological

英文关键词： MicroRNA；Radiation；DNA repair；Cell proliferation；Cell Migration