CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia
CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia
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DOI：
10.1053/gast.2002.36598
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发表时间：
2002-11-01
期刊：
影响因子：
29.4
通讯作者：
Fearon, ER
中科院分区：
文献类型：
--
作者：
Hinoi, T;Lucas, PC;Fearon, ER
背景和目标：CDX 2在小肠发育和分化过程中起着重要作用。一个Cdx 2等位基因的失活使小鼠易于发展结肠息肉，并且CDX 2表达的缺失是人类中一些低分化结肠癌的特征。相反，CDX 2的异常表达常见于胃和食管的肠上皮化生以及一些胃癌。为了更好地理解CDX 2的功能，我们试图定义CDX 2调控的基因。研究方法：HT-29结肠癌细胞与最低限度的内源性CDX 2表达工程表达外源性CDX 2，基因表达变化相对于对照细胞进行了评估，使用高密度寡核苷酸阵列。结果：HT-29中的肝肠（LI）-钙粘蛋白（钙粘蛋白17）基因被CDX 2强烈诱导。在其他结直肠癌细胞系中，内源性CDX 2和LI-钙粘蛋白表达具有良好的相关性。配体调节形式的CDX 2的激活迅速诱导LI-钙粘蛋白基因的表达，即使在蛋白质合成抑制剂的存在下。LI-钙粘蛋白基因的5 '侧翼区的分析定义了2个CDX 2响应元件，并且染色质免疫沉淀测定表明CDX 2结合元件。在原发性结直肠癌和胃肠道化生中，CDX 2和LI-钙粘蛋白表达密切相关。结论：CDX 2通过与基因5 '侧翼区的元件结合来调节胃肠道的正常、化生和肿瘤组织中的LI-钙粘蛋白基因表达。鉴于钙粘蛋白在形态发生和分化中的作用，LI-钙粘蛋白可能是肠细胞命运决定中介导CDX 2功能的关键因素。
Background & Aims: The intestine-specific caudal-related homeobox transcription factor CDX2 seems to play a key role in intestinal development and differentiation. Inactivation of one Cdx2 allele predisposes mice to develop colon polyps, and loss of CDX2 expression is a feature of some poorly differentiated colon carcinomas in humans. Conversely, aberrant CDX2 expression is often seen in intestinal metaplasias in the stomach and esophagus and in some gastric carcinomas. To better understand CDX2 function, we sought to define CDX2-regulated genes. Methods: HT-29 colon cancer cells with minimal endogenous CDX2 expression were engineered to express exogenous CDX2, and gene expression changes relative to control cells were assessed using high-density oligonucleotide arrays. Results: The gene for liver intestine (LI)-cadherin (cadherin 17) was strongly induced by CDX2 in HT-29. In other colorectal cancer lines, endogenous CDX2 and LI-cadherin expression were well correlated. Activation of a ligand-regulated form of CDX2 rapidly induced LI-cadherin gene expression, even in the presence of protein synthesis inhibitor. Analysis of the 5'-flanking region of the LI-cadherin gene defined 2 CDX2 responsive elements, and chromatin immunoprecipitation assays indicate CDX2 binds to the elements. In primary colorectal cancers and intestinal metaplasias in the stomach, CDX2 and LI-cadherin expression were tightly correlated. Conclusions: CDX2 regulates LI-cadherin gene expression in normal, metaplastic, and neoplastic tissues of the gastrointestinal tract via binding to elements in the 5'-flanking region of the gene. Given the well-established roles of cadherins in morphogenesis and differentiation, LI-cadherin may be a key factor mediating CDX2 function in intestinal cell fate determination.