Hypoxic exosomal HIF-1α-stabilizing circZNF91 promotes chemoresistance of normoxic pancreatic cancer cells via enhancing glycolysis.

Research has indicated that hypoxia profoundly contributes to chemoresistance of pancreatic cancer (PC), while the precise mechanism has not been fully elucidated. In this study, we report a hypoxic exosomal circular RNA (circRNA)-mediated mechanism of conferred chemoresistance in PC cells. Gemcitabine (GEM) resistance was enhanced in normoxic PC cells incubated with exosomes derived from hypoxic PC cells. CircRNA microarray displayed that circZNF91 was remarkably increased in hypoxic exosomes of PC cells compared with normoxic exosomes. Overexpression of circZNF91 obviously stimulated chemoresistance in PC cells, while knockdown of circZNF91 retarded the hypoxic exosome-transmitted chemoresistance. Mechanistically, the hypoxic-induced exosomal circZNF91 transmitted into normoxic PC cells could competitively bind to miR-23b-3p, which deprives the inhibition of miR-23b-3p on expression of deacetylase Sirtuin1 (SIRT1). Consequently, the upregulated SIRT1 enhanced deacetylation-dependent stability of HIF-1α protein, leading to glycolysis and GEM chemoresistance of recipient PC cells. In addition, we revealed that the increased circZNF91 in hypoxic exosome was attributed to the transcriptional regulation by HIF-1α. Coincidently, transmission of hypoxic exosomes into subcutaneous xenografts in nude mice obviously facilitated the chemoresistance of transplanted PC tumor, which could be reversed by depletion of circZNF91 or upregulation of miR-23b-3p. Furthermore, clinical data showed that circZNF91 was significantly upregulated in PC tissues and correlated with overexpression of glycolytic enzymes and short overall survival time. Collectively, exosomal circZNF91 can function as a cargo mediating the signal transmission between hypoxic and normoxic tumor cells to promote GEM chemoresistance of PC and may potentially serve as a therapeutic target.