Expression of a BTB/POZ Protein, NAC1, Is Essential for the Proliferation of Normal Cyclic Endometrial Glandular Cells and Is Up-regulated by Estrogen
Expression of a BTB/POZ Protein, NAC1, Is Essential for the Proliferation of Normal Cyclic Endometrial Glandular Cells and Is Up-regulated by Estrogen
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DOI：
10.1158/1078-0432.ccr-08-2134
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发表时间：
2009-02-01
影响因子：
11.5
通讯作者：
Miyazaki, Kohji
中科院分区：
文献类型：
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作者：
Ishibashi, Masako;Nakayama, Kentaro;Miyazaki, Kohji
目的：探讨BTB/POZ基因家族成员NAC1在人周期子宫内膜中的表达和定位。实验设计：采用免疫组织化学方法检测NAC1在正常周期子宫内膜中的表达，并对临床变量进行回顾性分析。为了探讨NAC1在正常子宫内膜癌细胞系(Ishikawa，HHUA；ER+，PR+)和原代培养的正常子宫内膜中表达的分子机制，我们用性类固醇诱导实验和NAC1基因敲除实验检测了NAC1在子宫内膜癌细胞系中的表达。10nmol/L 17β-雌二醇(E_2)可上调Ishikawa、HHUA和原代培养的正常子宫内膜细胞NAC1RNA和蛋白的表达。雌激素受体拮抗剂10182,780可显著抑制E2诱导的NAC1表达。在Ishikawa、HHUA和正常子宫内膜中，NAC1基因敲除均可抑制细胞生长和诱导细胞凋亡，这些细胞均表达NAC1。此外，在Ishikawa、HHUA和原代培养的正常子宫内膜细胞中，NAC1 siRNA显著抑制雌激素诱导的细胞增殖，而对照siRNA对这些细胞中的细胞生长都没有影响。结论：NAC1在功能上参与了E2诱导的正常子宫内膜腺细胞的生长。由于NAC1被认为具有致癌潜力，目前的发现可能为雌激素诱导子宫内膜癌的发生机制提供新的见解。
Purpose: The purpose of this study was to investigate the expression and localization of NAC1, a member of the BTB/POZ gene family in the human cyclic endometrium.Experimental Design: NAC1 expression in normal cyclic endometrium was assessed by immunohistochemistry, and data on clinical variables were collected by retrospective chart review. To elucidate the molecular mechanisms of NAC1 expression in the normal endometrium endometrial carcinoma cell lines (Ishikawa, HHUA; ER+, PR+) and primary cultured normal endometria were tested in a sex steroid induction assay and a NAC1 knockdown assay using si RNA.Results: Expression of NAC1 in glandular cells was significantly higher in the early and mid proliferative phases than in the other menstrual phases. Both NAC1 RNA and protein expression were up-regulated by treatment with 10 nmol/L 17 beta-Estradiol (E2) in Ishikawa, HHUA and primary cultured normal endometrial cells. The estrogen receptor antagonist 10 182,780 significantly attenuated E2-induced NAC1 expression. NAC1 gene knockdown inhibited cell growth and induced apoptosis in Ishikawa, HHUA, and normal endometria, all of which expressed NAC1. Furthermore, NAC1 siRNA significantly abrogated estrogen-driven cellular proliferation in Ishikawa, HHUA, and primary cultured normal endometrial cells, whereas the control siRNA had no effect on cell growth in any of these cells.Conclusions: These findings suggest that NAC1 is functionally involved in E2-induced cell growth of the normal endometrial glandular cells. Because NAC1 is thought to have oncogenic potential, the current findings may provide new insight into the mechanism of estrogen induced endometrial carcinogenesis.