Estrogen ‐ related receptor γ promotes the migration and metastasis of endometrial cancer cells by targeting S 100 A 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. Introduction Endometrial cancer (EC) is the most common gynecologic tumor in developed countries, with an increasing prevalence (1). It is estimated that 61,380 new cases and 10,920 deaths resulting from EC occurred in 2017 (2). Adenocarcinoma of the endometrium accounts for over 70% of all uterine cancers. Most patients (80%) are diagnosed with early disease and can be surgically cured. However, the outcome of advanced or recurrent cases remains far worse, and the adjuvant treatment options are quite limited (1). Discovery of novel targets is warranted to better understand the EC pathogenesis and to develop new therapeutic approaches for this disease. It is well known that tumor progression and metastasis are often linked to epithelial-mesenchymal transition (EMT). During this process, a more invasive cell phenotype is established, accompanied by alterations in the expression of many core molecules, particularly E-cadherin (3). Thus, it is worthwhile to explore the regulatory mechanism of EMT in the tumor biology of EC. S100 calcium binding protein A4 (S100A4) has been shown to be involved in biological functions that contribute to malignant tumors, such as proliferation, apoptosis, metastasis, angiogenesis and immune evasion (4). More importantly, S100A4 plays pivotal roles in tumor invasion by triggering EMT, mechanically serves as a downstream target gene of the wnt/β-catenin pathway, modulates membrane integrin signaling, and directly promotes cell motility through interaction with cytoskeletal proteins such as myosin, actin and tropomyosin (5-7). Elevated S100A4 expression has been found in many types of tumors and is closely related to poor outcome in tumor patients (8). Our previous research revealed that S100A4 is highly expressed in EC cells, and knockdown of S100A4 expression resulted in suppression of the migration and invasion capability of EC cells, which may partially occur via EMT-related modifications (9). However, the regulatory mechanisms of S100A4 expression in EC remain to be elucidated. Estrogen-related receptors (ERRs; ERRα, ERRβ and ERRγ) comprise a subgroup of orphan nuclear receptors that share highly homologous DNA-binding domains with Estrogen‐related receptor γ promotes the migration and metastasis of endometrial cancer cells by targeting S100A4 TENG HuA1*, XIAOXIAO WANG1*, SHuqI CHI1, YAN LIu1, DILu FENG1, YINGCHAO ZHAO2 and HONGbO WANG1 1Department of Obstetrics and Gynecology, and 2Cancer Center, union Hospital, Tongji Medical College, Huazhong university of Science and Technology, Wuhan, Hubei 430023, P.R. China Received November 28, 2017; Accepted May 15, 2018 DOI: 10.3892/or.2018.6471 Correspondence to: Professor Hongbo Wang, Department of Obstetrics and Gynecology, union Hospital, Tongji Medical College, Huazhong university of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei 430022, P.R. China E-mail: hb_wang1969@sina.com Professor Yingchao Zhao, Cancer Center, union Hospital, Tongji Medical College, Huazhong university of Science and Technology, 156 Wujiadun Road, Hankou, Wuhan, Hubei 430023, P.R. China E-mail: 2006xh0836@hust.edu.cn *Contributed equally