RBM15 Drives Breast Cancer Cell Progression and Immune Escape via m6A-Dependent Stabilization of KPNA2 mRNA.

Background: Breast cancer is the most frequently diagnosed cancer among women worldwide with high morbidity and mortality. Previous studies have indicated that RNA-binding motif protein-15 (RBM15), an N6-methyladenosine (m6A) writer, is implicated in the growth of breast cancer cells. Herein, we aimed to explore the function and detailed mechanism of RBM15 in breast cancer.

Methods: In this research, UALCAN databases were applied to analyze the expression of RBM15 or Karyopherin-2 alpha (KPNA2) in BRCA. RBM15 and KPNA2 mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR) assay. RBM15, KPNA2, and Programmed cell death ligand 1 (PD-L1) protein levels were measured using western blot. Cell proliferation, migration, and invasion were assessed using 5-ethynyl-2'-deoxyuridine (EdU) and Transwell assays. The biological role of RBM15 on breast cancer tumor growth was verified using the xenograft tumor model in vivo. Effects of breast cancer cells on the proliferation and apoptosis of CD8⁺ T cells were analyzed using flow cytometry. Interaction between RBM15 and KPNA2 was validated using methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assays.

Results: RBM15 and KPNA2 were highly expressed in breast cancer tissues and cell lines. Furthermore, RBM15 silencing might suppress breast cancer cell proliferation, migration, invasion, and lymphocyte immunity in vitro, as well as block tumor growth in vivo. At the molecular level, RBM15 might improve the stability and expression of KPNA2 mRNA via m6A methylation.

Conclusion: RBM15 might contribute to the malignant progression and immune escape of breast cancer cells partly by modulating the stability of KPNA2 mRNA, providing a promising therapeutic target for breast cancer.