Extracellular vesicle-encapsulated microRNA-761 enhances pazopanib resistance in synovial sarcoma

摘要

Abstract The development of drug resistance in tumor cells leads to relapse and distant metastasis. Secreted microRNAs (miRNAs) enclosed in extracellular vesicles (EVs) can act as intercellular messengers. The objective of our study was to elucidate the role of secreted miRNAs to better understand the regulatory network underlying pazopanib-resistance in synovial sarcoma cells. We performed a comprehensive analysis of secreted miRNA abundance in pazopanib treated/untreated synovial sarcoma cells from four different cell lines (SYO-1, HS-SYII, 1273/99, and YaFuSS) using microarray technology, and discovered miR-761 in EVs as a potential biomarker of pazopanib-resistance in synovial sarcoma. Furthermore, we showed that miR-761 putatively targeted three proteins, thyroid hormone receptor interactor 6 (TRIP6), lamin A/C (LMNA), and NAD-dependent protein deacetylase sirtuin-3 (SIRT3). Knockdown of any of these proteins was shown in previous studies to confer increased resistance to chemotherapeutic agents. Our findings provide new insight into the potential role of miR-761, an EV-secreted miRNA from synovial sarcoma cells, making it a potential candidate for use in sarcoma therapy in the future. Highlights ? MiR-761 in EVs is abundant in pazopanib-resistant synovial sarcoma cells. ? EVs derived from pazopanib-resistant cells spread resistance to recipient cells. ? Increased miR-761 abundance in EVs is associated with pazopanib resistance.