Role of CITED2, a novel ulcerative colitis specific gene, to colitis and carcinogenesis.

在溃疡性结肠炎中，患者的粘膜中显著检测到变种梭杆菌，该细菌大量产生的丁酸可诱导上皮细胞凋亡。在这里，我们确定了一个由丁酸诱导的基因，该基因特异性地存在于溃疡性结肠炎相关癌细胞系中。基因芯片和验证研究表明，CITED2基因特异性上调。CITED2可诱导P53乙酰化和P53依赖的细胞凋亡，并伴随CBP/p300的结合。在溃疡性结肠炎的炎症灶中，组织学上明显的炎症活动与CITED2的表达显著相关。另一方面，我们还发现在UC患者的结肠粘膜中诱导了OLFM4的表达，并且其表达与UC的组织学活动有关。综上所述，在体外模拟UC条件下，基于Percellome方法的基因芯片鉴定CITED2为溃疡性结肠炎相关蛋白。CITED2的激活可能通过激活P53诱导粘膜的凋亡和侵蚀，从而在溃疡性结肠炎的肠道细菌与粘膜炎症的联系中发挥关键作用。CITED2与OLFM4的相关性有待进一步研究。

In ulcerative colitis, Fusobacterium varium is significantly detected in patients' mucosa, and butyric acid, abundantly produced by the bacterium, induces epithelial apoptosis. Here, we identified a gene induced by butyric acid specifically in ulcerative colitis-associated cancer cell lines. cDNA microarray and the validation study revealed CITED2 to be specifically upregulated. CITED2 could be shown to induce p53 acetylation and p53-dependent apoptosis, accompanied by binding of CBP/p300.In inflammatory foci of ulcerative colitis, histologically evident inflammatory activity and CITED2 expression were significantly correlated. On the other hand, we also found olfactomedin 4(OLFM4) induced in the UC-patients' colonic mucosae, and its expression is correlated to the histological activity of UC. In conclusion, CITED2 was identified as ulcerative colitis-associated protein by cDNA microarray based on the Percellome method under UC-mimicking conditions in vitro. CITED2 activation may induce mucosal apoptosis and erosion by activating p53 and thus play a critical role in linking enteric bacteria with mucosal inflammation in ulcerative colitis. Further study of association of CITED2 and OLFM4 is remains to be clarified.