RBM8A confers oxaliplatin resistance in gastric cancer by maintaining EGFR mRNA stability

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• RNA-binding proteins (RBPs) regulate gene expression post-transcriptionally.
• The role of RBPs in chemotherapy resistance is not well understood.
• Gastric cancer (GC) often develops resistance to treatments like oxaliplatin.

Purpose of the Study:

• To identify RBPs involved in oxaliplatin resistance in GC.
• To elucidate the mechanism by which RBM8A confers chemoresistance.
• To evaluate RBM8A and its associated pathway as therapeutic targets in GC.

Main Methods:

• Conducted a siRNA screen of 40 RBM family members.
• Performed functional studies on RBM8A, including mRNA stabilization assays.
• Utilized single-cell RNA-seq and tissue microarrays for patient data analysis.
• Investigated therapeutic targeting using gefitinib (EGFR inhibitor) in vitro and in vivo.

Main Results:

• Identified RBM8A as a key regulator of oxaliplatin-induced DNA damage in GC.
• Demonstrated that RBM8A stabilizes epidermal growth factor receptor (EGFR) mRNA via eIF4A3 recruitment.
• Showed that RBM8A promotes DNA repair (NHEJ) and suppresses apoptosis, leading to chemoresistance.
• Found RBM8A enrichment in malignant cells and dual RBM8A/EGFR overexpression correlating with poor survival.
• Gefitinib treatment restored oxaliplatin sensitivity and inhibited RBM8A-driven tumor growth.

Conclusions:

• The RBM8A-eIF4A3-EGFR axis is a critical determinant of chemoresistance in gastric cancer.
• RBM8A is a druggable target and a prognostic biomarker for GC.
• Targeting this axis offers a potential therapeutic strategy for overcoming oxaliplatin resistance in GC.