The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers
The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers
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DOI：
10.1158/0008-5472.can-05-2881
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Richer, JK
中科院分区：
文献类型：
--
作者：
Spoelstra, NS;Manning, NG;Richer, JK
转录因子ZEB1（小鼠中的δ E2）与发育和肿瘤进展期间的细胞过程有关，包括上皮细胞向间质细胞的转化。缺失Δ EF1的小鼠在出生时存活，但表达插入Δ EF1基因的LacZ报告基因的杂合子存活并繁殖。使用这些小鼠，我们观察了ZEB 1启动子在处女子宫肌层，妊娠子宫的基质和肌层中的活性。ZEB1蛋白在卵巢切除小鼠的子宫肌层和子宫内膜基质中在孕激素或雌激素治疗后上调。在正常人子宫中，在月经周期的分泌阶段，子宫肌层和间质中的ZEB1蛋白增加。ZEB1没有。表达于正常子宫内膜上皮。在子宫恶性肿瘤中，我们发现ZEB 1（a）在来源于子宫肌层的恶性肿瘤（平滑肌瘤）中过表达，（B）在低级别子宫内膜样腺癌的肿瘤相关基质中过表达，（c）在侵袭性子宫内膜癌的肿瘤上皮细胞中异常表达。具体而言，在3级类囊腺癌和子宫乳头状浆液性癌中，ZEB 1可以在上皮来源的癌细胞以及间质中表达。在恶性苗勒管混合瘤中，肉瘤成分总是表达ZEB 1，并且癌成分也可以是阳性的。总之，ZEB1通常受雌激素和孕激素受体的调节，但在子宫癌中，它可能不再受类固醇激素受体的控制，并在上皮来源的肿瘤细胞中异常表达，支持ZEB1在与侵袭性肿瘤相关的上皮向间充质转化中的作用。
The transcription factor ZEB1 (delta EFI in mice) has been implicated in cellular processes during development and tumor progression including epithelial to mesenchymal transition. delta EF1 null mice the at birth, but heterozygotes expressing a LacZ reporter inserted into the delta EF1 gene live and reproduce. Using these mice, we observed ZEB1 promoter activity in the virgin myometrium, and stroma and myometrium of the pregnant uterus. ZEB1 protein is up-regulated in the myometrium and endometrial stroma after progesterone or estrogen treatment of ovariectomized mice. In the normal human uterus, ZEB1 protein is increased in the myometrium and stroma during the secretory stage of the menstrual cycle. ZEB1 is not. expressed in the normal endometrial epithelium. In malignancies of the uterus, we find that ZEB1 (a) is overexpressed in malignant tumors derived from the myometrium (leiomyosarcomas), (b) is overexpressed in tumor-associated stroma of low-grade endometrioid adenocarcinomas, and (c) is aberrantly expressed in the tumor epithelial cells of aggressive endometrial cancers. Specifically, in grade 3 endometrioid adenocarcinomas and uterine papillary serous carcinomas, ZEB1 could be expressed in the epithelial-derived carcinoma cells as well as in the stroma. In malignant mixed Mullerian tumors, the sarcomatous component always expresses ZEB1, and the carcinomatous component, can also be positive. In summary, ZEB1 is normally regulated by both estrogen and progesterone receptors, but in uterine cancers, it is likely no longer under control of steroid hormone receptors and becomes aberrantly expressed in epithelial-derived tumor cells, supporting a role for ZEB1 in epithelial to mesenchymal transitions associated with aggressive tumors.