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

Although aberrant activation of Hippo/YAP has been demonstrated to contribute to 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. Identifying effective treatment targets that modulate the Hippo/YAP axis to suppress development of GSRC is of critical importance.GPER was identified as highly overexpressed in GSRC and correlated with worse prognosis. Its activation facilitated tumor proliferation by YAP nuclear translocation and subsequent transcriptional activation. Mechanistically, GPER disrupted LATS1-mediated YAP phosphorylation by competitively binding to ARRB2, thereby enhancing YAP activity. Moreover, YAP bound to the GPER promoter, forming a positive feedback loop that reinforced oncogenic signaling.These findings revealed the key role of the GPER-YAP positive feedback loop in GSRC progression. Targeting this signaling axis, particularly via dual inhibition of GPER and YAP, offered a promising therapeutic strategy for GSRC.