Exosome-transmitted circIFNGR2 Modulates Ovarian Cancer Metastasis via miR-378/ST5 Axis

Cancer-associated fibroblasts (CAFs)-derived exosomes have emerged as a key driver of ovarian cancer (OVCA) tumor progression. The mechanisms behind the specific circular RNA (circRNA) activity encapsulated by CAF-generated exosomes (CAF-exo) requires to be elucidated. Herein, this study selected specific circRNA (hsa_circIFNGR2) molecules and aimed to clarify novel function of CAF-derived exosomal circIFNGR2 on growth, and metastasis of OVCA cells. In this study, we clarified that the exosomes of CAFs originating from human ovarian cancer hindered tumor cell proliferation, metastasis and EMT in vitro. Interestingly, CAFs directly transferred exosomes into OVCA cells to enrich intracellular circIFNGR2 levels. Biologically, activation of exosomal circIFNGR2 blocked cell proliferation, metastasis and EMT. Mechanistically, enhanced circIFNGR2 activated the miR-378/ST5 axis and directly inhibited the malignant evolution of tumor cells. Furthermore, rescue experiments evidenced that circIFNGR2 and ST5 were two essential participants in OVCA, concretely manifested in the co-culture of OVCA cells with exosomes that reversed the effects of intracellular circIFNGR2 and ST5 depletion. Finally, we observed that CAF-exo treatment hindered tumor growth and increased the size and number of metastatic nodules in mice. Our study revealed a previously unknown regulatory pathway whereby CAFs-derived exosomes delivered circIFNGR2 and inhibited the malignant progression of OVCA by circIFNGR2/miR-378/ST5 axis.