Dicer抑制结直肠癌发生的机制：靶向K-ras基因关键microRNA的发现及功能研究

项目名称： Dicer抑制结直肠癌发生的机制：靶向K-ras基因关键microRNA的发现及功能研究

项目编号： No.81472316

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： 柳玉红

作者单位： 南方医科大学

项目金额： 78万元

中文摘要： 近期我们发现，临床结直肠癌组织Dicer mRNA 表达下调，分化低的结直肠癌组织Dicer 蛋白表达明显缺失；肠粘膜上皮条件性Dicer純合敲除小鼠的生长、发育明显受抑，其肠粘膜有明显的炎症反应；化学诱导肠粘膜上皮条件性Dicer杂合敲除小鼠更易发生肠肿瘤甚至浸润性癌改变；对Dicer稳定敲除细胞进行microRNA表达谱分析发现，靶向K-ras基因的microRNA明显富集。基于此我们提出Dicer抑制结直肠癌发生的重要机制，通过靶向K-ras基因关键microRNA起作用。本研究以前期建立的肠粘膜上皮条件性Dicer 敲除小鼠的动物模型为基础，结合结直肠癌相关细胞系及结直肠癌临床组织标本，从整体动物模型、细胞模型及临床标本等方面阐明Dicer及其依赖的靶向K-ras基因关键microRNA在结直肠癌发生及演进中的作用。

中文关键词： C08_结；直肠肿瘤；非编码RNA；基因表达调控

英文摘要： We previously found that Dicer was down-regulated in the tumor tissues of colorectal cancer (CRC) and low expression of Dicer was most likely found in poor differentiated tumor tissues of CRC. Moreover, mice with intestinal specific knockout of Dicer showed inhibitory growth and development and severe inflammatory reaction in small intestine and large intestine. Notably, colorectal tumors were easy to be developed and even invasive adenocarcinoma of colon could be observed in chemical-induced Dicerloxp/+&Villin-Cre mice.Interestingly, microRNA profile analysis of Dicer Knockout cells discovered a group of microRNA targeting K-ras. Here, we suggested a key mechanism in which Dicer suppressed tumorigenesis of CRC by regulating a group of microRNA targeting K-ras gene. We will study the role of Dicer and its dependent microRNA in pathogenesis and progression of CRC in intestinal specific knockout of Dicer mouse model, cell models and clinical samples of CRC.

英文关键词： colorectal cancer;non-coding RNA;gene regulation