Heparanase confers temozolomide resistance by regulation of exosome secretion and circRNA composition in glioma.

The occurrence of temozolomide (TMZ) resistance is the main challenge in the management of glioma patients. Heparanase can mediate the secretion and function of exosomes, which are considered to be a promising molecular delivery system for cancer therapy. Therefore, this study aimed to investigate whether Heparanase-mediated delivery of exosomes was related to the TMZ resistance of glioma. Heparanase was up-regulated in TMZ-resistant glioma cells, and overexpression of Heparanase led to increased resistance of U87 cells to TMZ, while knockdown of Heparanase led to increased sensitivity of TMZ-resistant U251 cells (U251R) cells to TMZ. Heparanase promoted the secretion of exosomes from glioma cells, and co-culture with exosomes derived from Heparanase knockdown U251R cells partly restored the sensitivity of U251 cells to TMZ compared with exosomes derived from si-control transfected U251R cells. It was identified by circRNA microarrays that hsa_circ_0042003 was up-regulated in exosomes derived from U251R, which could be positively regulated by Heparanase. U251R cell-derived exosomal hsa_circ_0042003 conferred the resistance of U251 cells to TMZ. In vivo studies also showed that U251R cell-derived exosomes induced resistance of U251 cells to TMZ, and the combination of tail-injected exosomal si-Heparanase or eoxosomal si-hsa_circ_0042003 and intraperitoneal TMZ applied to nude mice abolished TMZ-resistance. Heparanase mediated the transfer of exosomal hsa_circ_0042003 from TMZ-resistant glioma cells to drug-sensitive cells, which contributed to the chemoresistance of glioma to TMZ. This article is protected by copyright. All rights reserved.