NR2F1 Regulates TGF-β1-Mediated Epithelial-Mesenchymal Transition Affecting Platinum Sensitivity and Immune Response in Ovarian Cancer.

Abstract

Simple SummaryIn ovarian cancer (OC), platinum-based therapy remains the front-line therapy, but drug resistance is common. In the current study, we analyzed two Gene Expression Omnibus (GEO) datasets to identify the responsible genes involved in the mechanism of platinum resistance. Thirteen co-upregulated genes and one co-downregulated gene were obtained. Among them, NR2F1 revealed the highest correlation with a poor prognosis. Mechanism research revealed that NR2F1 promotes epithelial-mesenchymal transition (EMT) through TGFβ-1 signaling, participating in platinum resistance. We also found that NR2F1 was positively correlated with the infiltration of immunosuppressive cancer-associated fibroblasts (CAFs). Higher expression of NR2F1 was correlated with a poorer response to immune check blockades including anti-PD-L1. In the future, by analyzing the expression status of NR2F1 and the effect of platinum and immunotherapy in the clinical setting, it is expected that NR2F1 will be established as an effective drug selection marker, guiding treatment selection in OC patients.The mechanism underlying platinum resistance in ovarian cancer (OC) remains unclear. We used bioinformatic analyses to screen differentially expressed genes responsible for platinum resistance and explore NR2F1′s correlation with prognostic implication and OC staging. Moreover, Gene-set enrichment analysis (GSEA) and Gene Ontology (GO) analyses were used for pathway analysis. Epithelial-mesenchymal transition (EMT) properties, invasion, and migration capacities were analyzed by biochemical methods. The association between NR2F1 and cancer-associated fibroblast (CAF) infiltration and immunotherapeutic responses were also researched. A total of 13 co-upregulated genes and one co-downregulated gene were obtained. Among them, NR2F1 revealed the highest correlation with a poor prognosis and positively correlated with OC staging. GSEA and GO analysis suggested the induction of EMT via TGFβ-1 might be a possible mechanism that NR2F1 participates in resistance. In vitro experiments showed that NR2F1 knockdown did not affect cell proliferation, but suppressed cell invasion and migration with or without cisplatin treatment through the EMT pathway. We also found that NR2F1 could regulate TGF-β1 signaling, and treating with TGF-β1 could reverse these effects. Additionally, NR2F1 was predominantly associated with immunosuppressive CAF infiltration, which might cause a poor response to immune check blockades. In conclusion, NR2F1 regulates TGF-β1-mediated EMT affecting platinum sensitivity and immune response in OC patients.