The tRF-33/IGF1 axis dysregulates mitochondrial homeostasis in HER2-negative breast cancer

Transfer RNA-derived small RNAs (tsRNAs), a recently identified noncoding RNA subset, are mainly classified into transfer RNA (tRNA)-derived small RNA fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs). tsRNAs dysregulation is frequently observed in numerous cancer types, suggesting involvement in tumorigenesis. However, their functions in breast cancer (BC) remain to be fully understood. Here, it was discovered that tRF-33-MEF91SS2PMFI0Q (tRF-33), derived from mature tRNA-Lys^TTT, was markedly upregulated in human epidermal receptor 2 (HER2)-negative BC cells and tissue samples. tRF-33 stimulated the proliferation, migration, and invasiveness of BC cells in vitro and facilitated tumor progression in vivo. Mechanistically, tRF-33 was found for the first time to bind directly to the 3'-UTR of IGF1, resulting in downregulation of both its mRNA and protein and thus affecting mitochondrial homeostasis and progression of BC. These results demonstrate a novel tsRNA modulatory mechanism and a potential direction for treating HER2-negative BC.NEW & NOTEWORTHY In this study, we identified differential expression of tRNA fragments in HER2-negative BC tissues compared with adjacent normal tissues, observing significant upregulation of an i-tRF type tRF-33-MEF91SS2PMFI0Q (tRF-33) in the tumor tissue. We also found that tRF-33 promoted tumorigenesis in BC cells. We demonstrated for the first time that IGF1 was a target gene of tRF-33 and also showed that the tRF-33/IGF1 axis impaired mitochondrial dynamics, thus affecting mitochondrial homeostasis and promoting HER2-negative BC progression.