Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Chemoresistance significantly contributes to treatment failure in bladder cancer.
• Identifying molecular mechanisms underlying drug resistance is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To elucidate the molecular mechanisms by which gemcitabine plus cisplatin (GEM/DDP) induces chemoresistance in bladder cancer.
• To investigate the role of OIP5 in conferring chemoresistance and its association with patient prognosis.
• To evaluate the therapeutic potential of a CRISPR/Cas9-based gene circuit targeting this pathway.

Main Methods:

• Investigated the effects of GEM/DDP on NF-κB signaling and OIP5 expression.
• Utilized molecular biology techniques to study protein interactions and transcriptional regulation (OIP5, TRIP12, PPP1CB, YBX1, IKKβ).
• Developed and tested a CRISPR/Cas9 engineered gene circuit for real-time monitoring and intervention of chemoresistance in vivo.

Main Results:

• GEM/DDP therapy activates NF-κB signaling, leading to OIP5 upregulation.
• OIP5 promotes chemoresistance by recruiting TRIP12 to degrade PPP1CB, enhancing YBX1 activity and drug-resistance gene expression.
• A negative feedback loop involving PPP1CB degradation and IKKβ phosphorylation further amplifies NF-κB signaling and OIP5 expression.
• Elevated OIP5 expression correlates with chemoresistance and poor prognosis in bladder cancer patients.
• The CRISPR/Cas9 gene circuit effectively inhibited tumor growth in vivo by inducing OIP5 knockout.

Conclusions:

• The OIP5-mediated pathway is a key driver of GEM/DDP chemoresistance in bladder cancer.
• OIP5 expression serves as a prognostic biomarker for bladder cancer.
• Engineered gene circuits targeting this pathway offer a promising strategy for overcoming chemoresistance and enhancing cancer therapy.