The novel tRNA-derived fragment, tiRNA-Met, inhibits the malignant progression of triple-negative breast cancer by regulating RANBP3L via a targeted interaction with SNRPA

BACKGROUND: tRNA-derived fragments (tRFs) have emerged as significant noncoding RNAs in cancer biology; however, their roles and mechanisms in triple-negative breast cancer (TNBC) remain inadequately characterized. METHODS: tRF and tiRNA sequencing, real-time quantitative polymerase chain reaction (RT-qPCR), fluorescence in situ hybridization (FISH), and subcellular fractionation were used to explore the expression and characteristic of tiRNA-Met in TNBC. The biological functions of tiRNA-Met were assessed using CCK-8 assays, colony formation assays, and Transwell assays in vitro, alongside mouse xenograft models in vivo. RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), western blot, ubiquitination assays, RNA sequencing, actinomycin D assays, immunofluorescence, immunohistochemical staining, and rescue experiments were performed to explore the regulatory mechanisms of tiRNA-Met in TNBC. RESULTS: and was primarily localized in the cytoplasm. Its expression was significantly downregulated in TNBC tumor tissues compared with adjacent normal tissues. Overexpression of tiRNA-Met markedly inhibited the proliferation, migration, and invasion of TNBC cells; whereas, its reduced expression elicited opposite effects. In addition, tiRNA-Met overexpression suppressed TNBC cell growth in vivo. Mechanistically, tiRNA-Met directly interacted with the RNA recognition motif 2 (RRM2) domain of small nuclear ribonucleoprotein A (SNRPA), promoting SNRPA protein degradation via the ubiquitin/proteasome pathway. This interaction enhanced the stability of Ran-binding protein 3-like (RANBP3L) mRNA, resulting in increased RANBP3L expression and subsequent inhibition of the mTORC1/RPS6 signaling pathway. CONCLUSIONS: Our study identified tiRNA-Met as a novel anti-oncogenic tRF and elucidated its mechanism for inhibiting the malignancy of TNBC. tiRNA-Met directly bound to SNRPA, promoting its degradation and stabilizing RANBP3L mRNA, ultimately leading to the inhibition of the mTORC1 signaling pathway. These findings position tiRNA-Met as a promising candidate for diagnostic and therapeutic applications in TNBC.