Downregulation of NEAT1 sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis

Chemoresistance is a major cause of treatment failure in pancreatic cancer (PC). It has been demonstrat-ed that epithelial-to-mesenchymal transition (EMT) is closely related to drug resistance in PC; however, the underly-ing mechanisms are not yet fully understood. Recently found evidence has suggested that nuclear-enriched abun-dant transcript 1 (NEAT1) is involved in the development of chemoresistance. However, the role and mechanism of NEAT1 in PC gemcitabine resistance remain unknown. In the present study, we first established two independent gemcitabine-resistant (GR) PC cell lines, PANC-1/GR and SW1990/GR. We found that GR cells displayed markedly enhanced migration and invasion abilities, decreased expression of E-cadherin, and upregulation of N-cadherin, Vimentin, Snail, ZEB1, and ZEB2. Our findings suggested that downregulation of NEAT1 enhanced the sensitivity of GR cells to gemcitabine by reversing the EMT process. Mechanistically, NEAT1 mediates ZEB2 mRNA expression through sponging miR-506-3p. Downregulation of NEAT1 can reverse the EMT process of GR PC cells by reducing the expression of ZEB2, thus enhancing the sensitivity of GR PC cells to gemcitabine. These findings were further confirmed in a nude mouse xenograft model. Taken together, downregulation of NEAT1 sensitized the GR PC cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis. These results provide the novel evidence for understanding the function and molecular mechanism of NEAT1, and a new direction for improving the chemo-therapeutic effects in PC.

Automated summary

The study showed that downregulation of NEAT1 sensitized gemcitabine-resistant pancreatic cancer cells by mediating the expression of ZEB2 through sponging miR-506-3p. NEAT1 downregulation reversed the EMT process in pancreatic cancer cells, enhancing their sensitivity to gemcitabine. These findings provide novel insights into the function and molecular mechanism of NEAT1 and offer a new approach to improving chemotherapy effectiveness in pancreatic cancer.