ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma
ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma
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DOI：
10.1038/modpathol.2013.93
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发表时间：
2013-11-01
期刊：
影响因子：
7.5
通讯作者：
Palacios, Jose
中科院分区：
文献类型：
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作者：
Romero-Perez, Laura;Angeles Lopez-Garcia, M.;Palacios, Jose
未分化子宫内膜癌是一种侵袭性很强的高级别子宫内膜癌，常常被忽视。本研究旨在分析这些子宫内膜癌发生的分子基础改变，重点关注与去分化相关的分子。我们评估了120例肿瘤：57例1级和2级子宫内膜样癌，15例3级子宫内膜样癌，27例子宫内膜浆液性癌和21例未分化子宫内膜癌。我们发现在未分化癌中DNA错配修复缺陷的发生率很高（38%），p53过表达的发生率中等（接近33%）。与特征性类胡萝卜素表型相反，在未分化亚型中E-钙粘蛋白表达显著下调。定量甲基化研究驳回CDH 1启动子高甲基化的机制，负责这种变化的基因表达，而免疫组化显示，E-钙粘蛋白阻遏物ZEB 1经常过度表达（62%）在未分化的子宫内膜癌。这一发现伴随着miR-200家族microRNA表达的急剧下调，miR-200家族是ZEB 1的众所周知的靶点。此外，在未分化的子宫内膜癌中，上皮间质转化标志物，如N-钙粘蛋白、胞浆p120和骨粘连蛋白的表达增强。此外，在侵袭性子宫内膜肿瘤如子宫内膜浆液性癌和癌性肉瘤中表达的上皮-间质转化调节因子HMGA 2在>20%的未分化癌中表达。这些结果表明，ZEB 1过表达，与E-cadherin和miR-200下调，以及间充质标志物的表达可能会增加未分化子宫内膜癌的转移潜力，导致预后不良。此外，我们的观察表明，E-cadherin和ZEB 1的免疫组化分析可以帮助更积极的未分化的子宫内膜癌3级卵巢样癌的鉴别诊断。
Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (similar to 33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis of E-cadherin and ZEB1 can aid in the differential diagnosis of the more agressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas.