Msx1 loss suppresses formation of the ectopic crypts developed in the Apc-deficient small intestinal epithelium
Msx1 loss suppresses formation of the ectopic crypts developed in the Apc-deficient small intestinal epithelium
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DOI：
10.1038/s41598-018-38310-y
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发表时间：
2019-02-07
影响因子：
4.6
通讯作者：
Korinek，Vladimir
中科院分区：
文献类型：
--
作者：
Horazna，Monika;Janeckova，Lucie;Korinek，Vladimir
人类结直肠癌发展的第一步是Wnt信号通路的异常激活。Wnt信号转导过度激活主要是由编码途径负调节因子的腺瘤性结肠息肉病（APC）基因的功能丧失突变引起的。为了鉴定受Apcloss影响的基因，我们对从携带条件性Apcallele的小鼠中分离的肠上皮进行了表达谱分析。编码转录因子msh同源框1（Msx 1）的基因在Apcinactivation后显示出强烈的上调。APC缺陷上皮的组织学分析显示，在小肠中，Msx 1蛋白仅定位于异位隐窝，即，在绒毛上异常定位的增殖细胞的口袋中。Msx1基因的消融导致异位隐窝的消失和分化细胞的丢失。此外，从Msx1缺陷细胞产生的肿瘤显示改变的形态，让人想起绒毛状腺瘤。在人类肿瘤标本中，MSX1在结肠肿瘤中的表达显著增加，并在病变向结直肠癌进展过程中呈下降趋势。总之，这些结果表明Msx1代表了肠道肿瘤发生的新标志物。此外，我们描述了以前未知的Msx1依赖性异位隐窝形成和细胞分化之间的关系。
The first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway. Wnt signaling hyperactivation is predominantly caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene that encodes the pathway negative regulator. In order to identify genes affected by theApcloss, we performed expression profiling of intestinal epithelium isolated from mice harboring a conditionalApcallele. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation uponApcinactivation. Histological analysis of the Apc-deficient epithelium revealed that in the small intestine, the Msx1 protein was localized exclusively in ectopic crypts, i.e., in pockets of proliferating cells abnormally positioned on the villi. Ablation of theMsx1gene leads to the disappearance of ectopic crypts and loss of differentiated cells. Moreover, tumors arising from Msx1-deficient cells display altered morphology reminiscent of villous adenomas. In human tumor specimens,MSX1displayed significantly increased expression in colonic neoplasia with a descending tendency during the lesion progression towards colorectal carcinoma. In summary, the results indicate that Msx1 represents a novel marker of intestinal tumorigenesis. In addition, we described the previously unknown relationship between the Msx1-dependent formation of ectopic crypts and cell differentiation.