Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430023, P.R. China.
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430023, P.R. China.
Oncol Rep. 2018 Aug;40(2):823-832. doi: 10.3892/or.2018.6471. Epub 2018 Jun 4.
S100 calcium binding protein A4 (S100A4) is a well‑established tumor metastasis mediator in various malignancies, including endometrial cancer (EC). However, the regulatory mechanism underlying S100A4 expression remains elusive. In the present study, by analyzing public datasets and clinical samples, we found that estrogen‑related receptor γ (ERRγ) was upregulated and positively correlated with S100A4 transcription in EC. ERRγ knockdown inhibited S100A4 expression and promoted the expression of its downstream target E‑cadherin, and vice versa. Mechanistic studies indicated that ERRγ enhanced the promoter activity of S100A4 to facilitate its transcription. In addition, knockdown of ERRγ suppressed migration and invasion of EC cells in vitro, while ectopic ERRγ expression promoted migration and invasion of EC cells in vitro and tumor growth in vivo. Importantly, restoration of S100A4 expression prevented EC cells from undergoing ERRγ‑mediated changes in these biological features. In addition, synchronous changes in S100A4 and ERRγ expression were observed after incubation with estrogen. Overall, ERRγ may exert oncogenic activity mainly associated with aggressiveness of EC by activating S100A4 transcription and thus may be a novel therapeutic target in EC.
S100 钙结合蛋白 A4（S100A4）是多种恶性肿瘤中一种成熟的肿瘤转移介质，包括子宫内膜癌（EC）。然而，S100A4 表达的调控机制仍不清楚。在本研究中，通过分析公共数据集和临床样本，我们发现雌激素相关受体γ（ERRγ）在 EC 中上调，并与 S100A4 转录呈正相关。ERRγ 敲低抑制 S100A4 的表达并促进其下游靶标 E-钙黏蛋白的表达，反之亦然。机制研究表明，ERRγ 增强了 S100A4 启动子的活性，从而促进其转录。此外，ERRγ 的敲低抑制了 EC 细胞在体外的迁移和侵袭，而 ERRγ 的异位表达促进了 EC 细胞在体外的迁移和侵袭以及体内的肿瘤生长。重要的是，S100A4 的表达恢复阻止了 EC 细胞发生 ERRγ 介导的这些生物学特征的变化。此外，在孵育雌激素后观察到 S100A4 和 ERRγ 表达的同步变化。总体而言，ERRγ 通过激活 S100A4 转录可能主要发挥与 EC 侵袭性相关的致癌活性，因此可能是 EC 的一种新的治疗靶点。
