CDX2 regulates multidrug resistance 1 gene expression in malignant intestinal epithelium.
CDX2 regulates multidrug resistance 1 gene expression in malignant intestinal epithelium.
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DOI：
10.1158/0008-5472.can-09-4701
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发表时间：
2010-09-01
期刊：
影响因子：
11.2
通讯作者：
Ohdan H
中科院分区：
文献类型：
--
作者：
Takakura Y;Hinoi T;Oue N;Sasada T;Kawaguchi Y;Okajima M;Akyol A;Fearon ER;Yasui W;Ohdan H
尾部相关同源盒转录因子CDX 2在肠道发育和分化中起关键作用。CDX 2杂合突变小鼠发生结肠息肉，CDX 2表达缺失见于人类结肠癌的一个亚群。转基因小鼠胃中的异位CDX 2表达促进肠上皮化生，并且CDX 2表达经常在胃和食管的肠上皮化生中检测到。我们试图确定CDX 2调节基因，以增强对CDX 2功能的了解。HT-29结肠直肠癌细胞具有最小的内源性CDX 2表达，并且产生具有异位CDX 2表达的HT-29细胞。基于微阵列的基因表达研究显示，CDX 2激活了多药耐药1（MDR 1/P-glycoprotein/ABCB 1）基因。MDR 1基因是CDX 2的直接转录靶点的证据，包括MDR 1报告基因构建和染色质免疫沉淀分析。RNA干扰介导的CDX 2抑制降低了内源性MDR 1表达。在各种结直肠癌细胞系和人体组织中，内源性MDR 1表达与CDX 2表达密切相关。HT-29细胞中CDX 2的过度表达揭示了对MDR 1的已知底物长春新碱和紫杉醇的耐药性增加，这被MDR 1抑制剂维拉帕米逆转。这些数据表明，CDX 2通过与启动子区元件结合直接调节MDR 1基因表达。因此，CDX 2可能是重要的MDR 1的基础表达，调节药物的排泄和吸收在下胃肠道，以及对化疗药物的多药耐药的CDX 2阳性胃肠道癌。
The caudal-related homeobox transcription factor CDX2 has a key role in intestinal development and differentiation. CDX2 heterozygous mutant mice develop colonic polyps, and loss of CDX2 expression is seen in a subset of colon carcinoma in man. Ectopic CDX2 expression in the stomach of transgenic mice promotes intestinal metaplasia, and CDX2 expression is frequently detected in intestinal metaplasia in the stomach and esophagus. We sought to define CDX2-regulated genes to enhance knowledge of CDX2 function. HT-29 colorectal cancer cells have minimal endogenous CDX2 expression, and HT-29 cells with ectopic CDX2 expression were generated. Microarray-based gene expression studies revealed that the Multidrug Resistance 1 (MDR1/P-glycoprotein/ABCB1) gene was activated by CDX2. Evidence that the MDR1 gene was a direct transcriptional target of CDX2 was obtained, including analyses with MDR1 reporter gene constructs and chromatin-immunoprecipitation assays. RNA interference-mediated inhibition of CDX2 decreased endogenous MDR1 expression. In various colorectal cancer cell lines and human tissues, endogenous MDR1 expression was well correlated to CDX2 expression. Over-expression of CDX2 in HT-29 cells revealed increased resistance to MDR1's known substrate, vincristine and paclitaxel, which was reversed by an MDR1 inhibitor, verapamil. These data indicate that CDX2 directly regulates MDR1 gene expression via binding to elements in the promoter region. Thus, CDX2 is probably important for basal expression of MDR1, regulating drug excretion and absorption in the lower gastrointestinal tract, as well as for multidrug resistance to chemotherapy reagent in CDX2-positive gastrointestinal cancers.