GPER1 Silencing Suppresses the Proliferation, Migration, and Invasion of Gastric Cancer Cells by Inhibiting PI3K/AKT-Mediated EMT.

En Xu,Zijian Li,Feng Wang,Xiaofeng Lu,Chang Zheng,Chaoyu Jiang,Xingzhou Wang,Zhi Yang,Ji Miao,Shangce Du,Wenxian Guan,Xuefeng Xia,Yizhou Wang

doi:10.3389/fcell.2020.591239

Abstract

G protein coupled estrogen receptor (GPER1) is a membrane estrogen receptor, belonging to the seven-transmembrane G protein-coupled receptors family, and has important biological functions in cancer. However, the functional role of GPER1 in gastric cancer (GC) remain incompletely understood. In the present study, we employed gene set enrichment analysis and discovered that GPER1 expression was concomitant with EMT process and was positively correlated with activation of the PI3K/AKT pathway in GC. Knockdown of GPER1 with siRNA suppressed the proliferation, migration, and invasion of AGS and MGC-803 GC cells. Knockdown of GPER1 also downregulated the mesenchymal markers N-cadherin and vimentin, upregulated E-cadherin, an epithelial marker, and suppressed expression of the Snail, Slug and Twist1 transcription factors, indicating that knockdown of GPER1 inhibited EMT. Moreover, 740Y-P, a PI3K activator, reversed the effects of GPER1 knockdown on EMT processes. Overexpression of GPER1 with plasmid can further prove these findings. In summary, these data demonstrate that GPER1 inhibition suppresses the proliferation, migration, and invasion of gastric cancer cells by inhibiting PI3K/AKT-mediated EMT. Our study elucidated the function of GPER1 in gastric cancer, and we identified PI3K/AKT-mediated EMT as a novel mechanism by which GPER1 contributes to proliferation, migration, and invasion of gastric cancer. These data suggest that combining inhibition of GPER1 and PI3K may be a potential therapeutic approach to inhibit gastric cancer metastasis.

Highlights

Gastric cancer is the third leading cause of cancer-related death worldwide, and is the third leading cause of cancer mortality in China (Chen et al, 2016; Bray et al, 2018)
We examined the expression of GPER1 by western blot in four gastric cancer cell lines, including MGC-803, AGS, BGC-823, and MKN-45 and found that GPER1 was highly expressed in the AGS and MGC-803 cell lines (Figure 1C)
GPER1 is a specific estrogen receptor that is independent of the classical estrogen receptors, such as ERα and ERβ

Summary

Introduction

Gastric cancer is the third leading cause of cancer-related death worldwide, and is the third leading cause of cancer mortality in China (Chen et al, 2016; Bray et al, 2018). GPER1 mediated the proliferation of hepatocytes via PI3K and mTOR signaling, and chemical inhibition or knockdown of GPER1 significantly reduced tumor growth in a zebrafish model (Chaturantabut et al, 2019). G1, a GPER1 agonist, inhibited the proliferation and apoptosis of A549 lung cancer cells mediated by oxidant and antioxidant molecules (Kurt et al, 2015), and suppressed the migration and angiogenesis of triple negative breast cancer cells through suppressing the NF-κB/IL-6 pathway (Liang et al, 2017).GPER1 expression is associated with poorer prognosis in patients with gastric cancer (Wesolowska et al, 2016), but the specific role of GPER1 in gastric cancer development and progression is not well-understood

Methods

Results

Conclusion