miR-34a 介导的炎症壁龛和血管壁龛对肠干细胞增殖和肠癌恶性转化的研究

Paneth cells are thought as unique niche for colon stem cell self-renewal. However, during tumorigenesis, colon stem cells expand much faster than Paneth cells, indicating there are other niches to support colon stem cell proliferation. But what are they? We previously found deficiency of miR-34a promoted colon stem cell self-renewal and colon cancer progression. When miR-34a was lost, colon cancer stem cells (CCSCs) transdifferentiated into vascular endothelial cells, which in turn promoted CCSC self-renewal. Our recent data further showed that pathogenic Citrobacter rodentium initiates adenocarcinomas in miR-34a deficient mice. In addition, we found Ascl2+ colon stem cells are significantly amplified in the colitis associated colon cancer with TH17 cells surrounded. The phenomena raise many questions. For example, what is the mechanism of miR-34a-mediated CCSC transdifferentiation and how endothelial cells promote CCSC self-renewal. What is the role of miR-34a to mediate TH17 cell differentiation and recruitment in colon cancers? Do the TH17 cells provide niche for colon stem cell self-renewal? What is the clinical relevance of miR-34a–mediated inflammatory and vascular niche for colon cancer initiation and progression? We will take advantage of organoid culture and transgenic mice, integrate technologies including bioinformatics, cell biology and molecular biology to challenge the questions in our study.

正常肠干细胞依赖潘氏细胞提供壁龛进行自我更新。肠癌中，肠干细胞的增殖明显多于潘氏细胞。那么除了潘氏细胞，其他什么细胞还可以为肠干细胞的增殖提供壁龛呢？申请人长期从事非编码RNA在肠癌干细胞增殖分化和肠癌发生方面的研究并发现：（1）miR-34a缺失诱导肠癌干细胞转分化为血管内皮细胞促进干细胞的自我更新；（2）炎症诱导miR-34a缺失小鼠产生肠癌，且肠癌中富集肠干细胞和TH17细胞。本项目将以类器官培养、基因敲除小鼠为手段，系统研究miR-34a 介导的炎症壁龛和血管壁龛对肠干细胞增殖和肠癌发生影响。具体解决以下问题： miR-34a缺失介导肠癌干细胞向血管内皮细胞的转分化及血管内皮细胞作为肠癌干细胞壁龛的分子机制；miR-34a缺失介导TH17细胞在肠癌中的富集及TH17细胞作为肠干细胞壁龛的分子机制；miR-34a作为枢纽中心介导的炎症壁龛和血管壁龛对肠癌发生和发展的影响及其临床意义。

本研究利用肠炎-肠癌转化模型，发现正常肠干细胞向肠癌干细胞转化新机制。研究发现鼠类柠檬酸杆菌介导的肠炎能够促使miR-34a缺失小鼠产生肠癌。miR-34a的缺失促进了肠干细胞在肠癌中快速扩增，招募大量TH17细胞浸润在干细胞周围。miR-34a通过靶向T细胞表面IL6R和IL23R抑制Th17细胞的分化和增殖，并且靶向肠上皮细胞分泌的CCL22，抑制Th17细胞向肠上皮的浸润。不仅如此，Th17细胞通过分泌IL-17激活下游STAT3信号通路促进结肠类器官的生长。IL-17的中和抗体可以抑制鼠类柠檬酸杆菌介导miR-34a缺失小鼠肠癌的发生。临床数据显示Th17的浸润和miR-34a表达呈负相关。. 本研究首次发现非编码RNA同时调控免疫细胞和肠上皮细胞，免疫细胞和肠上皮细胞的作用促进肠癌的发生。此外，Th17细胞作为壁龛促进肠干细胞的增殖，丰富了之前肠干细胞需要潘氏细胞作为壁龛，促进自我更新的认知。

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