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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283111 | GEO | 2025/03/28

REPOSITORIES: GEO

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Regulation of Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer

Project description:The Hippo pathway is crucial in organ size control and tumorigenesis. The dys-regulation of Hippo/YAP axis is vastly observed in gastric cancer, while the effective therapeutic targets for Hippo/YAP axis are still not clear. It is important and urgent to identify reliable drug targets and the underlying mechanisms, which could inhibit the activity of Hippo/YAP axis and gastric cancer progression. In our current study, we demonstrate the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator for Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block the tumorigenesis in gastric cancer. Molecular studies reveal that the activation of CXCR7 could dephosphorylate YAP, facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assay shows that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates CXCR7 is both the upstream signaling and downstream target for Hippo/YAP axis in gastric cancer. In general, we identified a novel positive feedback loop between CXCR7 and Hippo/YAP axis, while blockade of CXCR7 could be a plausible strategy for gastric cancer.

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