GPR107-EGFR crosstalk promotes ovarian cancer metastasis by regulating IL-6 release via PI3K/AKT/NF-κB signaling...

Ovarian cancer (OVCA) has the highest mortality rate among all gynecological malignancies. Epidermal growth factor receptor (EGFR) is commonly overexpressed in epithelial OVCA (30-98%) and is significantly positively correlated with poor patient prognosis. However, therapeutic drugs targeting EGFR have not shown promising results, indicating the existence of other potential mechanisms. G-protein-coupled receptor (GPCR) families were reported to crosstalk with EGFR, jointly affecting the activation of downstream signaling pathway networks. G protein-coupled receptor 107 (GPR107), a novel orphan GPCR, is overexpressed in tumors and is involved in cancer progression. Little is known about the role of GPR107 in OVCA progression. In this study, the underlying mechanism of GPR107-EGFR crosstalk and its critical function in OVCA progression were investigated. GPR107, which was highly expressed in OVCA and was associated with advanced clinical stages, could interact with EGFR on the cell membrane and promoted the invasion, migration, and epithelial mesenchymal transition (EMT) of OVCA. Mechanistically, GPR107-EGFR crosstalk promoted EGFR phosphorylation and downstream PI3K/AKT/NF-κB activation, resulting in autocrine IL-6 secretion, which facilitated OVCA metastasis both in vitro and in vivo. Monoclonal antibodies targeting IL-6 could inhibit OVCA metastasis induced by GPR107. In conclusion, our study highlights the importance of GPR107-EGFR crosstalk in OVCA metastasis by clarifying the function and molecular mechanism of GPR107-EGFR crosstalk, and provides a novel direction for developing new treatment strategies for OVCA.