USP15 Promotes Pancreatic Cancer Progression and Cisplatin Resistance By Activating DNA Damage Repair

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cisplatin (DDP) is a primary chemotherapy for pancreatic cancer (PC).
• Resistance to DDP, often mediated by DNA damage repair (DDR) pathways, limits treatment efficacy.
• The role of Ubiquitin-specific peptidase 15 (USP15) in PC and its association with DDP resistance are not well understood.

Purpose of the Study:

• To investigate the expression, clinical significance, and functional role of USP15 in pancreatic cancer.
• To elucidate the mechanism by which USP15 influences DDP resistance.
• To assess USP15 as a potential prognostic biomarker and therapeutic target in PC.

Main Methods:

• Analysis of USP15 expression in PC tissues and cell lines using RT-qPCR, Western blot, and immunohistochemistry.
• Functional studies including in vitro (colony formation, flow cytometry) and in vivo (mouse xenograft model) assays to evaluate USP15's effect on DDP resistance.
• Co-immunoprecipitation (Co-IP) to confirm USP15-POLE3 interaction and assessment of DNA damage levels via immunofluorescence and comet assays.

Main Results:

• USP15 was significantly upregulated in PC tissues and associated with poor patient prognosis.
• Overexpression of USP15 enhanced DDP resistance in PC cells both in vitro and in vivo.
• USP15 interacts with POLE3, suppressing its degradation and thereby enhancing DDP-induced DNA damage repair, linking USP15 to DDR pathways.

Conclusions:

• USP15 is upregulated in pancreatic cancer and serves as a negative prognostic factor.
• USP15 promotes DDP resistance in PC by stabilizing POLE3 and facilitating DNA damage repair.
• USP15 represents a potential therapeutic target for overcoming DDP resistance in pancreatic cancer.