MiR-139-5p调控肠道菌群介导的新疆地区结肠炎相关结肠癌发生发展的机制及其靶向递送应用研究

During the increased tumor incidence of chronic colitis, intestinal flora plays a key role in the development of colitis associated colon cancer. It is found that the abnormal expression of miRNA and the activation of beta -Catenin/TCF-4 signaling pathway are important links in the development of intestinal flora mediated colitis associated colon cancer, but the detail of this mechanism is unclear. In our previous work, we found that intestinal flora imbalance in colitis associated colon cancer model, and low expression level of miR-139-5p and high expression level of TCF-4 in colorectal cancer tissues compared with adjacent tissues. MiR-139-5p knockout mice were higher sensitive to DSS-induced colitis and enhanced formation of intestinal neoplasia was observed when mice were exposed to AOM/DSS treatment. Based on our previous study, we conducted the following three areas studied: (1) clear the correlation between the intestinal flora, miR-139-5p and TCF-4 in colitis associated colon cancer colon tissue; (2) reveal the molecular mechanism of miR-139-5p and TCF-4 negative feedback regulated the occurrence and development of intestinal flora mediated colitis associated colon cancer; (3) protamine-modified nanodiamond is used as a transport vector while miR-139-5p, linked to the nucleic acid adapter EpCAM, is a carrier with targeted anti-cancer effect. We are to investigate the compatibility, cytotoxicity and targeted therapeutic effect of this composite vector. This study is of great significance to provide new ideas for prevention and treatment of colon cancer.

新疆地区慢性结肠炎的肿瘤发病率日益增高，研究发现miRNA异常表达和β-Catenin/TCF-4信号通路激活是肠道菌群介导的结肠炎相关结肠癌发生发展的重要环节，但其具体分子机制尚不明确。我们前期发现，结肠炎相关结肠癌模型中肠道菌群失衡，miR-139-5p下调，而TCF-4上调; miR-139-5p敲除小鼠对结肠炎相关结肠癌发病敏感性增加。本项目以人结肠癌组织、急性结肠炎及结肠炎相关结肠癌小鼠模型、miR-139-5p-/-小鼠为研究对象，开展以下三个方面的研究: 明确肠道菌群、miR-139-5p与TCF-4在结肠炎相关结肠癌结肠组织的相关性；揭示miR-139-5p调控肠道菌群介导的结肠炎相关结肠癌发生发展的分子机制；制备核酸适配体EpCAM修饰的miR-139-5p纳米脂质体靶向药物，并研究这一复合载体动物活体内靶向治疗效果。该研究对于预防和靶向治疗结肠癌有着重要的意义。

新疆地区慢性结肠炎的肿瘤发病率日益增高，研究发现miRNA异常表达和β-Catenin/TCF-4信号通路激活是肠道菌群介导的结肠炎相关结肠癌发生发展的重要环节，但其具体分子机制 尚不明确。我们前期发现，结肠炎相关结肠癌模型中肠道菌群失衡，miR-139-5p下调，而TCF-4上调; miR-139-5p敲除小鼠对结肠炎相关结肠癌发病敏感性增加。本项目以人结肠癌组织、急性结肠炎及结肠炎相关结肠癌小鼠模型、miR-139-5p-/-小鼠为研究对象，开展以下研究:  miR-139-5p与TCF-4在结肠炎相关结肠癌结肠组织的相关性；揭示 miR-139-5p调控肠道菌群介导的结肠炎相关结肠癌发生发展的分子机制；制备核酸适配体EpCA M修饰的miR-139-5p纳米脂质体靶向药物，并研究这一复合载体动物活体内靶向治疗效果。研究结果表明，miR-139-5p激活Wnt /β-catenin/ TCF通路，E2-2基因反向上调Wnt信号分子，在结肠炎及结肠癌临床样本的实验中发现，miR‐139-5p水平随着肿瘤恶性程度的升高而降低，推测miR‐139-5p可能在结肠癌细胞侵袭和转移中起到逆转调节作用。核酸适配体EpCAM 修饰的miR-139-5p 纳米脂质体靶向药物EpCAM Apt-NLP -miR-139-5p，进一步证实miR-139-5p对结肠癌细胞的靶向抑制转移作用，并且该纳米转运系统在测试剂量下在体内不会引起明显的全身毒性或其他生理并发症，miR-139-5p可能成为临床结肠癌治疗的新靶向药物。该研究对于预防和靶向治疗结肠癌有着重要的意义。