Chen Yuan, Wang Shao-Xin, Mu Rui, Luo Xue, Liu Zhao-Shan, Liang Bing, Zhuo Hai-Long, Hao Xiao-Peng, Wang Qiong, Fang Di-Feng, Bai Zhao-Fang, Wang Qian-Yi, Wang He-Mei, Jin Bao-Feng, Gong Wei-Li, Zhou Tao, Zhang Xue-Min, Xia Qing, Li Tao
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; Department of Digestive, Navy General Hospital, 6 Fucheng Road, Beijing 100048, China.
Cell Rep. 2014 Jun 26;7(6):1982-93. doi: 10.1016/j.celrep.2014.05.007. Epub 2014 May 29.
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.
CUEDC2是一种含CUE结构域的蛋白质，可调节炎症反应，但其在肿瘤发生中的作用仍知之甚少。在此，我们报告CUEDC2是巨噬细胞功能的关键调节因子，对预防结肠炎相关肿瘤发生至关重要。在巨噬细胞分化过程中，CUEDC2表达显著上调，而CUEDC2缺陷会导致促炎细胞因子过度产生。巨噬细胞中CUEDC2的水平受miR-324-5p调控。我们发现Cuedc2基因敲除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易感性增加是由于缺乏CUEDC2的巨噬细胞功能障碍所致。此外，我们发现Cuedc2基因敲除小鼠更容易发生结肠炎相关癌症。重要的是，在人类结肠癌的巨噬细胞中几乎检测不到CUEDC2表达，而这种CUEDC2表达降低与白细胞介素-4和miR-324-5p的高水平有关。因此，CUEDC2在调节巨噬细胞功能中起关键作用，并且与结肠炎和结肠肿瘤发生均相关。
