[GPER1 regulates M2 macrophage polarization through the MYC pathway to influence gastric cancer progression]

Objective G protein-coupled estrogen receptor 1 (GPER1) has been reported to exert tumor-suppressive effects in various malignancies. However, the mechanism by which GPER1 modulates macrophage M2 polarization via the myelocytomatosis oncogene (MYC) signaling pathway and its impact on gastric cancer (GC) progression remains poorly understood. This study aims to explore the role of the GPER1-MYC-interleukin 10 (IL-10) axis in GC. Methods Bioinformatic analyses were conducted to assess GPER1 expression levels and associated signaling pathways. AGS and HGC-27 gastric cancer cell lines with stable GPER1 overexpression or knockdown were generated, using normally cultured cells as controls. Cell proliferation, migration, and invasion were evaluated using the Cell Counting Kit-8 (CCK-8), wound healing, and Transwell^TM assays, respectively. Western blotting was performed to examine MYC pathway activation, and the MYC-specific inhibitor 10058-F4 was used for mechanistic validation. A Transwell^TM co-culture system was established to simulate tumor-macrophage interactions. Flow cytometry was used to quantify the proportion of M2 macrophages, and IL-10 secretion was measured via ELISA. Results GPER1 expression was significantly downregulated in GC tissues and showed a negative correlation with MYC signaling activity. Knockdown of GPER1 promoted malignant phenotypes in gastric cancer cells, whereas GPER1 overexpression exerted suppressive effects. Mechanistically, GPER1 inhibited M2 macrophage polarization and reduced GC cell proliferation, invasion, and migration by downregulating IL-10 expression via MYC suppression. Notably, the MYC inhibitor reversed the tumor-promoting effects induced by GPER1 knockdown and enhanced the antitumor effects of GPER1 overexpression. Conclusion GPER1 modulates macrophage M2 polarization through the MYC-IL-10 axis, thereby affecting gastric cancer progression. These findings indicate GPER1 as a potential therapeutic target for gastric cancer intervention.