Dysregulation of the MiR-324-5p-CUEDC2 Axis Leads to Macrophage Dysfunction and Is Associated with Colon Cancer
Dysregulation of the MiR-324-5p-CUEDC2 Axis Leads to Macrophage Dysfunction and Is Associated with Colon Cancer
复制标题
miR-324-5p-CUEDC2 轴的失调会导致巨噬细胞功能障碍，并与结肠癌相关。
DOI：
10.1016/j.celrep.2014.05.007
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发表时间：
2014-06-26
期刊：
影响因子：
8.8
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Chen, Yuan;Wang, Shao-Xin;Li, Tao
CUEDC2是一种含有线索结构域的蛋白质，它调节炎症，但它在肿瘤发生中的作用仍然知之甚少。在这里，我们报告CUEDC2是巨噬细胞功能的关键调节因子，对于预防结肠炎相关肿瘤的发生至关重要。在巨噬细胞分化过程中，CUEDC2的表达显著上调，CUEDC2缺乏会导致促炎细胞因子的过度产生。巨噬细胞的CUEDC2水平受miR-324-5P的调节。我们发现Cuedc2KO小鼠对葡聚糖硫酸钠诱导的结肠炎更敏感，巨噬细胞移植结果表明，缺乏CUEDC2的巨噬细胞功能障碍导致易感性增加。此外，我们发现Cuedc2KO小鼠更容易患结肠炎相关癌症。重要的是，在人类结肠癌的巨噬细胞中几乎检测不到CUEDC2的表达，这种降低的CUEDC2表达与高水平的IL-4和miR-324-5p有关。因此，CUEDC2在调节巨噬细胞功能方面起着至关重要的作用，并与结肠炎和结肠肿瘤的发生有关。
CUEDC2, a CUE-domain-containing protein, modulates inflammation, but its involvement in tumorigenesis is still poorly understood. Here, we report that CUEDC2 is a key regulator of macrophage function and critical for protection against colitis-associated tumorigenesis. CUEDC2 expression is dramatically upregulated during macrophage differentiation, and CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is modulated by miR-324-5p. We find that Cuedc2 KO mice are more susceptible to dextran-sodium-sulfate-induced colitis, and macrophage transplantation results suggest that the increased susceptibility results from the dysfunction of macrophages lacking CUEDC2. Furthermore, we find that Cuedc2 KO mice are more prone to colitis-associated cancer. Importantly, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p. Thus, CUEDC2 plays a crucial role in modulating macrophage function and is associated with both colitis and colon tumorigenesis.