Tumor Exosome-transmitted LncRNA CATED Promotes Platinum-resistant in High-grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) represents the most lethal type of gynecological cancer, with platinum resistance being a serious challenge in HGSOC treatment. Long non-coding RNA (lncRNA) plays critical regulatory roles in the occurrence and development of various cancers, including HGSOC. Here, using RNA sequencing of tumor exosomes from HGSOC patients, we identified lncRNA CATED was significantly upregulated in both tumors and tumor-derived exosomes in platinum-resistant HGSOC, and low CATED level correlated with good prognosis. Functionally, CATED enhanced cisplatin resistance via promoting cell proliferation and decreasing apoptosis both in vitro and in vivo. These effects could also be transferred via CATED-overexpressing exosomes from donor cells and tumor exosomes from HGSOC patients. Mechanistically, CATED bound to and upregulated DHX36 via PIAS1-mediated SUMOylation at K105 site, and elevated DHX36 increased the downstream RAP1A protein levels by enhancing RAP1A mRNA translation, consequently activating MAPK pathway to promote platinum resistance in HGSOC. ASO-mediated knockdown of CATED reversed the platinum resistance in exosome-transferring mouse models through DHX36-RAP1A-MAPK pathway. Overall, these findings offer new insights into the critical roles of exosomal lncRNAs in platinum resistance, and indicate that CATED may be a potential target of HGSOC treatment.