MIMP调控miR-21-Ras/MAPK通路抑制具核梭杆菌致肠上皮细胞癌变的机制研究

项目名称： MIMP调控miR-21-Ras/MAPK通路抑制具核梭杆菌致肠上皮细胞癌变的机制研究

项目编号： No.81472262

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： 秦环龙

作者单位： 同济大学

项目金额： 75万元

中文摘要： 利用前期研究发现具核梭杆菌（Fn）在大肠癌(CRC)患者肠道粘膜、粪便中丰度显著增高及miR-21在炎症介导肿瘤机制中起关键作用的基础上，进一步明确Fn丰度在CRC不同病理阶段的临界阈值与规律性变化；利用基因沉默技术构建CRC细胞（miR-21敲除）和动物模型（miR-21敲除或IL-10敲除联合诱癌剂DSS/AOM）并进行体内外Fn干预实验，验证Fn丰度增高究竟是CRC的致病因素还是伴发现象，并阐明Fn致肠上皮细胞癌变的分子机制；分析前期研究发现的乳酸菌微小膜蛋白（MIMP）对感染Fn的CRC细胞和动物模型的保护作用，希望通过阐明MIMP与Fn竞争结肠上皮细胞甘露糖受体，抑制Fn对结肠上皮细胞的黏附，从而阻断miR-21-Ras/MAPK通路，发挥抗癌作用的分子机制，为将来利用Fn判断CRC发病风险和研发抗菌药物MIMP防治CRC提供理论基础。

中文关键词： 大肠癌；具核梭杆菌；乳酸菌微小膜蛋白；信号通路；分子机制

英文摘要： Recent studies have identified overrepresentation of Fusobacterium nucleatum in colorectal cancer tissues, but it is not yet clear whether this is pathogenic or an epiphenomenon.In our previous study, we have showed the key molecular mechanisms of prevention and treatment of intestinal inflammation and tumorigenesis through p38 MAPK signaling pathway using L.Plantarum Micro Integral Membrane Protein (MIMP).In addition, We have screened colorectal cancer(CRC) and matched normal tissue specimens using 16S rRNA sequencing and found marked over-representation of Fusobacterium nucleatum(Fn) sequences in tumors relative to control specimens. Moreover,we have verified that the overexpression of miR-21 in patients with ulcerative colitis impairs intestinal epithelial barrier function through targeting RhoB and miR-21 is involved in the regulation of colitis- associated colon cancer .Both of MIMP and miR-21 are involved in the Ras/MAPK sinaling pathway.On the basis of the preliminary results, we are seeking the clinical applications about Fn in CRC. We try to clarify the protective biological characteristics of the MIMP in the Fusobacterium nucleatum induced carcinogenesis via targeting mannose receptor and downregulating miR-21-Ras/MAPK signaling pathway through in vitro and in vivo experiments.Meanwhile, we are trying to explore the pathogenic role of Fn in patients with inflammatory bowel disease and CRC and AOM/DSS treated IL-10 knock-out or miR-21 knock-out mice model.The study may provide potential clinical applications in CRC prevention and therapy.

英文关键词： Colorectal cancer;Fusobacterium nucleatum;MIMP;signaling pathway;molecular mechanism