A miR-34a-guided, tRNA(i)(Met)-derived, piR_019752-like fragment (tRiMetF31) suppresses migration and angiogenesis of breast cancer cells via targeting PFKFB3

Although we recently demonstrated that miR-34a directly targets tRNA(i)(Met) precursors via Argonaute 2 (AGO2)-mediated cleavage, consequently attenuating the proliferation of breast cancer cells, whether tRNA(i)(Met) fragments derived from this cleavage influence breast tumor angiogenesis remains unknown. Here, using small-RNA-Seq, we identified a tRNA(i)(Met)-derived, piR_019752-like 31-nt fragment tRiMetF31 in breast cancer cells expressing miR-34a. Bioinformatic analysis predicted 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) as a potential target of tRiMrtF31, which was validated by luciferase assay. tRiMetF31 was downregulated, whereas PFKFB3 was overexpressed in cancer cell lines. Overexpression of tRiMetF31 profoundly inhibited the migration and angiogenesis of two breast cancer cell lines while slightly inducing apoptosis. Conversely, knockdown of tRiMetF31 restored PFKFB3-driven angiogenesis. miR-34a was downregulated, whereas tRNA(i)(Met) and PFKFB3 were upregulated in breast cancer, and elevated PFKFB3 significantly correlated with metastasis. Our findings demonstrate that tRiMetF31 profoundly suppresses angiogenesis by silencing PFKFB3, presenting a novel target for therapeutic intervention in breast cancer.