Pancreatic cancer is a highly aggressive digestive malignancy and gemcitabine (GEM)-based chemotherapy remains a cornerstone of its treatment despite widespread resistance. The present study employed human pancreatic cancer cell lines to construct a hypoxia model, exosomes were isolated and characterized via ultracentrifugation, microRNA (miR)-301a expression was detected using reverse transcription-quantitative PCR, GEM resistance was evaluated via the Cell Counting Kit-8 assay and the molecular mechanisms were validated by western blotting. The present study results demonstrated that under hypoxic stress, pancreatic cancer cells displayed morphological adaptations typical of cellular stress responses, upregulated miR-301a expression and markedly enhanced GEM resistance. Hypoxia increases the number of exosomes, which can transfer miR-301a to normoxic pancreatic cancer cells. Under normoxic conditions, inhibiting miR-301a expression markedly increased the sensitivity of pancreatic cancer cells to GEM. Furthermore, miR-301a promoted the development of drug resistance by regulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression. In conclusion, the present study revealed a novel mechanism by which hypoxia-derived exosomal miR-301a promotes GEM resistance in pancreatic cancer by regulating ACSL4. These findings provide a novel potential target to reverse GEM resistance, with theoretical and practical implications for future studies.
Keywords: exosomes; gemcitabine resistance; hypoxic microenvironment; microRNA-301a; pancreatic cancer.
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