Akademik Veri Yönetim Sistemi
MOKAD 10. MULTIDISIPLINARY CANCER RESEARCH CONGRESS, Eskişehir, Türkiye, 8 - 11 Mayıs 2025, ss.61, (Özet Bildiri)
Unveiling miR-770-5p/PRMT5 axis: A Novel Tumor Suppressor Axis on Regulation of KLF4 Mediated EGFR Signaling in TNBC
Senem Noyan1, Bala Gur Dedeoglu1, Alp Can2, Mehmet Alikaşifoğlu3
1Ankara University Biotechnology Institute
2Ankara University Faculty of Medicine, Department of Histology and Embryology
3Hacettepe University Faculty of Medicine, Department of Medical Genetics
Introduction and Aim: Triple negative breast cancer has (TNBC) overexpressed EGFR, and this makes it an attractive therapeutic target in TNBC. PRMT5, which is a histone methyl transferase is shown to be upregulated in breast cancers. Targeting epigenetic processes to alter their role in tumorigenesis and/or malignancy could be a promising therapeutic strategy to treat or prevent breast cancer. The aim of this study is to clarify how miR-770-5p regulates EGFR signaling through PRMT5 in TNBC cells.
Materials and Methods: qRT-PCR, western blotting, time-lapse imaging of cell morphology, immunofluorescence and luciferase reporter assays were employed to validate the underlying mechanisms of miR-770-5p/PRMT5/KLF4 axis. RNA-FISH was performed for miR-770-5p and PRMT5 localization. Bioinformatics and statistical analyses were performed to evaluate this axis.
Results and Discussion: Overexpression of miR-770-5p significantly decreased both total and phosphorylated EGFR levels, along with reduced activation of the PI3K and MAPK pathways, including AKT and ERK. In contrast, inhibition of miR-770-5p led to the upregulation of these signaling proteins, supporting its tumor suppressor role. Furthermore, miR-770-5p was shown to directly regulate PRMT5, which plays a crucial role in EGFR regulation. Bioinformatics analyses and experimental results, including RNA-FISH and luciferase assays, confirmed the direct interaction between miR-770-5p and PRMT5, leading to reduced PRMT5 expression. Further investigation revealed that miR-770-5p appears to interfere with the PRMT5/KLF4/EGFR axis. miR-770-5p's effect on this axis was studied using pharmacological inhibition of PRMT5, demonstrating that combining PRMT5 inhibition with miR-770-5p significantly reduced TNBC cell proliferation and EGFR expression. To investigate the effect of miR-770-5p on the PRMT5/KLF4 axis, subcellular fractionation revealed an increased cytoplasmic/nuclear ratio of KLF4 and a reduction in PRMT5 expression in the cytoplasm upon miR-770-5p treatment. These results suggest miR-770-5p influences PRMT5-mediated KLF4 cellular localization.
Conclusion: miR-770-5p regulates EGFR overexpression through modulation of the PRMT5/KLF4 axis, providing insights into potential therapeutic strategies for controlling TNBC progression.
Key words: miR-770-5p; Triple negative breast cancer; Epigenetic regulation; PRMT5; KLF4; EGFR signaling