Homeodomain protein CDX2 regulates COX-2 expression in colorectal cancer
Homeodomain protein CDX2 regulates COX-2 expression in colorectal cancer
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DOI：
10.1016/j.bbrc.2004.01.020
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发表时间：
2004-02-27
影响因子：
3.1
通讯作者：
Kwon, TK
中科院分区：
文献类型：
--
作者：
Kim, SP;Park, JW;Kwon, TK
CDX2是一种肠道特异的肿瘤抑制基因，编码同源结构域转录因子，参与多种发育、增殖和分化过程。此外，CDX2在部分原发结直肠癌中的表达降低。相反，环氧合酶-2(COX-2)在人类结直肠癌中经常上调。然而，CDX2下调和COX-2上调之间的分子关系尚不清楚。在这里，我们发现CDX2通过与核因子-kappaB相互作用下调COX-2启动子的活性。CDX2的异位表达抑制了PMA诱导的COX-2启动子活性，且呈剂量依赖关系。此外，PMA处理大肠癌细胞后，内源性CDX2水平显著降低，内源性COX-2水平显著升高，且呈剂量依赖关系。此外，CDX2被发现与核因子-kappaB的p65亚单位共沉淀，并抑制p65诱导的结肠癌细胞中核因子-kappaB的最小启动子活性。这些结果提示CDX2的表达降低可能通过增强NF-kappaB介导的炎症基因如COX-2参与了结直肠癌的发生。(C)2004 Elsevier Inc.保留所有权利。
CDX2 is an intestine-specific tumor suppressor gene encoding homeodomain-containing transcription factor, which is involved in a variety of developmental, proliferating, and differentiating processes. Moreover, the expression of CDX2 is reduced in a subset of primary colorectal cancers. In contrast, cyclooxygenase-2 (COX-2) is often up-regulated in human colorectal cancers. However, the molecular relationship between CDX2 down-regulation and COX-2 up-regulation is unknown. Here we show that CDX2 down-regulates COX-2 promoter activity by interacting with NF-kappaB. The ectopic expression of CDX2 was found to suppress PMA-induced COX-2 promoter activity in a dose-dependent manner. In addition, the treatment of colorectal cancer cells with PMA resulted in significant reduction in the level of endogenous CDX2 and a significant increase in the level of endogenous COX-2, in a dose-dependent manner. Furthermore, CDX2 was found to co-immunoprecipitate with the p65 subunit of NF-kappaB and to inhibit p65-induced NF-kappaB minimal promoter activity in colon cancer cells. These results suggest that reduced CDX2 expression may be involved in colorectal carcinogenesis by enhancing NF-kappaB-mediated inflammatory genes such as COX-2. (C) 2004 Elsevier Inc. All rights reserved.