Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett's esophagus
Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett's esophagus
复制标题
DOI：
10.1038/sj.onc.1209338
复制
发表时间：
2006-05-18
期刊：
影响因子：
8
通讯作者：
Benhattar, J.
中科院分区：
文献类型：
--
作者：
Clement, G.;Braunschweig, R.;Benhattar, J.
在巴雷特食管（BE）的肿瘤进展过程中，已有Wnt信号通路异常激活的报道。然而，APC和CTNNB1基因的突变却很少被观察到。在这项研究中，我们对正常食管黏膜以及BE患者的癌前病变和肿瘤病变中Wnt配体、卷曲受体和APC的表达模式，以及APC、SFRP1和SFRP2启动子基因的甲基化状态进行了研究。在所有BE样本以及95%的食管腺癌（EAC）中都发现了APC启动子甲基化。APC的完全甲基化与表达缺失相关。在EAC中，无论APC是否表达，都观察到β -连环蛋白的核转位。WNT2在异型增生和EAC中的表达高于BE，26例EAC中有20例（77%）显示WNT2高表达。SFRP1甲基化发生在所有BE样本以及96%的EAC中，而SFRP2在73%的正常食管鳞状上皮黏膜样本中发生甲基化。总之，（1）Wnt信号的关键调节因子的改变在BE的发病机制中很常见；（2）在BE中，APC和SFRP1基因因启动子甲基化而失活；（3）从低级别异型增生到EAC的进展过程中，WNT2基因上调。
Aberrant activation of the Wnt signaling pathway has been reported during neoplastic progression in Barrett's esophagus (BE). However, mutations in APC and CTNNB1 genes were rarely observed. In this study, expression pattern of Wnt ligands, Frizzled receptors and APC, as well as the methylation status of the APC, SFRP1 and SFRP2 promoter genes were investigated in normal esophageal mucosa and in preneoplastic and neoplastic lesions of BE patients. Promoter methylation of APC was found in all BE samples and in 95% of esophageal adenocarcinomas (EAC). Full methylation of APC correlated with lack of expression. In EAC, nuclear translocation of ss-catenin was observed regardless of the expression of APC. WNT2 expression was higher in dysplasia and EAC than in BE, with 20/26 (77%) of the EAC showing high expression of WNT2. SFRP1 methylation occurred in all BE samples and in 96% of EAC, while SFRP2 was methylated in 73% of the normal squamous esophageal mucosa samples. In conclusion, (1) alterations of key regulators of the Wnt signaling are frequent in the pathogenesis of BE; (2) the APC and SFRP1 genes are inactivated by promoter methylation in BE; (3) the WNT2 gene is upregulated along the progression from low-grade dysplasia to EAC.