Estrogen-Induced Stromal FGF18 Promotes Proliferation and Invasion of Endometrial Carcinoma Cells Through ERK and Akt Signaling

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Abstract

Jian Wu,1,2 Xiang Tao,3,4 Hong Zhang,5 Xiang-Hua Yi,1 Yin-Hua Yu4 1Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, People's Republic of China; 2Department of Pathology, Gongli Hospital, Second Military Medical University, Shanghai 200135, People's Republic of China; 3Department of Pathology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200032, People's Republic of China; 4Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China; 5Department of Pharmacy, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, People's Republic of ChinaCorrespondence: Xiang Tao Email tutufoliage@hotmail.comHong Zhang Email Hongzh97@tongji.edu.cnObjective: The aim of this study was to evaluate whether estrogen promoted the proliferation and invasion of endometrial carcinoma (EC) cells through paracrine FGFs in endometrial stromal cells (ESCs).Patients and Methods: We screened gene alterations in a primary ESC culture after 10 nM estrogen treatment using an Agilent mRNA microarray. We knocked down stromal FGF18 expression in a co-culture system and aimed to explore the contribution of E2-induced stromal FGF18 to the proliferation and invasion of EC cells. To determine the effective receptors and detailed downstream signaling of FGF18, we co-cultured estrogen-treated hESCs with FGFR1-, FGFR2-, FGFR3- or FGFR4-knockdown Ishikawa cells. Finally, we detected FGF18 expression in clinical samples, including several primary cultures of different ESCs and a series of tissue microarrays (TMAs) of 90 patients with EC.Results: A few genes altered significantly in estrogen-treated primary ESCs, but only FGF18 was noticeably enhanced among the FGF family genes. Knockdown of FGF18 expression in hESCs inhibited the promoting effect of FGF18 on the proliferation and invasion of EC cells. FGF18 bound FGFR2 and FGFR3 in Ishikawa cells to activate downstream ERK and Akt pathways and to promote the viability of EC cells. The FGF18-FGFR2 and FGF18-FGFR3 pathways had close correlations with Survivin and CD44V6 expression but not with P53. Primary ESCs of endometrioid EC (EEC, type I EC) had higher FGF18 expression than ESCs of normal endometrium (NE), endometrial atypical hyperplasia (EAH) and type II EC.Conclusion: Estrogen induced FGF18 in ESCs to promote the proliferation and invasion of EC cells, and FGFR inhibitors should be considered as promising candidate targets for EC treatment.Keywords: FGF18, paracrine, proliferation, invasion, endometrial stromal cells, ESCs, endometrial carcinoma, EC