miR-31在小肠干细胞和结直肠癌中的功能和机制研究

In response to irradiation, a small subset of intestinal stem cells survive due to its irradiation-resistant capacity, and are activated to generate the injury epithelium, which is similar to the cancer recurrence process that cancer stem cells are radiation-resistant, and regenerate tumors. Elucidating mechanisms underlying radiation resistance and activation of intestinal stem cells can help uncover the underlying principles of epithelial regeneration and tumorigenesis. In our preliminary data, we found that miR-31 is highly expressed in intestinal stem cells and colon cancer tissues, drives intestinal stem cell self-renewal during homeostasis and acts as an oncogene promoting intestinal tumorigenesis. During regeneration, miR-31 protects intestinal stem cells against irradiation and apoptosis, and activates the survived dormant stem cells to repair the injury epithelium in response as an epithelial-intrinsic coordinator of niche signals. In this proposal, we utilize miR-31 gain- and loss-of-function mouse models and intestinal tumor mouse models, as well as human colonic cancer tissue samples to investigate the in vivo role of miR-31 in normal intestinal stem cells and colorectal cancer development. Particularly, we plan to clarify its mechanism underlying miR-31-mediated radiation resistance and activation of dormant stem cells. This research is highly significant to provide scientific evidences for the diagnosis and therapy of colorectal cancer, and to develop new targets for cancer recurrence as well.

在辐射损伤过程中，一小部分小肠干细胞能抵抗辐射存活下来，并被激活修复损伤的上皮组织，这与癌干细胞抗放射治疗引起的癌症复发具有相似特征。探究干细胞抵抗辐射和被激活的分子机制有助于深入认识组织再生和癌症复发过程。前期工作中，我们发现miR-31在小鼠小肠干细胞和人结肠癌中特异地高表达，其在生理条件下能促进小肠干细胞自我更新，在肿瘤发生过程中促进肿瘤生长。而且，miR-31具有抵抗辐射和激活静息态干细胞的功能，通过调控多个信号通路参与干细胞驱动的肠道上皮再生过程。因此，本课题拟利用miR-31基因敲除小鼠、转基因过表达小鼠、干细胞谱系追踪小鼠和小肠肿瘤小鼠模型，结合人类结直肠癌组织和临床样本相关分析，进一步揭示miR-31在正常肠道干细胞和结直肠癌发生发展过程中的体内功能，以及其抵抗辐射和激活静息态干细胞的分子机制。为临床结直肠癌诊断生物标记、治疗药物设计和复发防治提供新的靶点和科学依据。

本项目利用多种转基因小鼠模型系统解析了miR-31在肠道干细胞和肠癌中的功能机制，并在此基础上建立了治疗结直肠癌的基于miR-31靶向递送药物。具体研究成果如下：.第一、在辐射损伤后，miR-31具有保护小肠静息态干细胞免于凋亡和促进干细胞激活的双重功能。miR-31首先通过抑制Gsk3β和p38保护小肠干细胞免于凋亡；随后通过抑制BMP信号并激活Wnt信号促进存活的小肠干细胞进行快速增殖。.第二、miR-31在结直肠癌中的表达水平异常升高，并作为促癌基因发挥功能。miR-31一方面能够同时靶向下调多个炎症因子受体而抑制炎症反应过程，一方面还能够通过激活Wnt和Yap信号通路促进肠上皮再生和肿瘤进展。.第三、们还成功设计出sOKGM-PS结直肠癌靶向载药体系，通过该载药系统递送miR-31模拟物能够有效修复上皮损伤并抑制结肠肿瘤的发生和发展，展现出重要的临床应用价值。.以上研究成果发表在eLife、Gastroenterology和Theranostics等期刊上。此外，相关研究（标记项目号）还发表在The EMBO journal、Cell Research、Cell Reports等期刊。