Down-regulation of USP22 reduces cell stemness and enhances the sensitivity of pancreatic cancer cells to cisplatin by inactivating the Wnt/β-catenin pathway.

Objective: Pancreatic cancer (PC) has the worst prognosis of all common cancers worldwide. This study was intended to investigate the role of ubiquitin specific peptidase 22 (USP22) in cisplatin sensitivity of PC cells and its regulatory mechanism.

Methods: The expression of USP22 and the toxicity of cisplatin to PC cells were detected. The two cell lines AsPC-1 and CAPAN-1 with the most differential drug resistance were selected. By down-expressing USP22 in CAPAN-1 cells and over-expressing USP22 in AsPC-1 cells, the survival rate of PC cells treated with cisplatin was detected. The mRNA expressions of stem cell markers, cell stemness, migration ability and apoptosis of PC cells were detected. The expression of Wnt/β-catenin pathway related proteins was detected. The role of the Wnt/β-catenin pathway in PC cell stemness and cisplatin sensitivity was explored after adding the inhibitor HLY78 and activator DKK1.

Results: USP22 was highly-expressed in PC cells, and the sensitivity of PC cells to cisplatin was negatively-correlated with USP22 expression. Downregulation of USP22 raised the sensitivity of PC cells to cisplatin, reduced the levels of stem cell markers, reduced the tumor sphere formation and migration, and promoted apoptosis. Silencing USP22 inhibited the Wnt/β-catenin pathway. Inhibition of USP22 reduced the cell stemness and augmented the sensitivity of PC cells to cisplatin by inhibiting the Wnt/β-catenin pathway.

Conclusion: Silencing USP22 can inhibit the Wnt/β-catenin pathway to reduce cell stemness and enhance the sensitivity of PC cells to cisplatin.