Regulatory mechanisms of the Hippo/YAP axis by G-protein coupled estrogen receptor in gastric signet-ring cell carcinoma

Although aberrant activation of the Hippo/YAP axis has been implicated in the development of gastric cancer, functional studies of this cascade in the context of gastric signet-ring cell carcinoma (GSRC) remain absent. Our previous single-cell sequencing results showed that G protein-coupled estrogen receptor (GPER) is overexpressed in GSRC, and this overexpression is associated with aberrant activation of the Hippo/YAP axis. In this study, we integrated in vitro cytological functional assays with GSRC cell lines and in vivo xenograft nude mice models to elucidate the functional implications of GPER in GSRC. The overexpression of GPER was identified as being associated with more unfavorable outcomes in GSRC. Its activation facilitated tumor proliferation by YAP nuclear translocation and subsequent transcriptional activation. Mechanistically, GPER inhibited LATS1-mediated YAP phosphorylation by competitively binding to ARRB2, thereby enhancing YAP activity. Moreover, YAP was shown to bind to the GPER promoter, forming a positive feedback loop that reinforced oncogenic signaling. Pharmacological inhibition of GPER using G-15 reduced YAP activation and effectively attenuated tumor aggressiveness, highlighting the GPER-YAP feedback loop as a potential therapeutic target for GSRC. This study underscores the pivotal role of the GPER-YAP positive feedback loop in GSRC and proposes dual inhibition of GPER and YAP as a promising therapeutic strategy for GSRC.