tRNA-derived fragments (tRFs) have been defined as a novel class of small noncoding RNAs. tRFs have been reported to be deregulated in
cancer, but their biologic function remains to be fully understood. We have identified a new tRF (named tRF3E), derived from mature
tRNAGlu, that is specifically expressed in healthy mammary glands but not in
breast cancer (BC). Consistently, tRF3E levels significantly decrease in the blood of patients with
epidermal growth factor receptor 2 (HER2)-positive BC reflecting
tumor status (control > early
cancer > metastatic
cancer). tRF3E down-regulation was recapitulated in Δ16HER2 transgenic mice, representing a BC preclinical model. Pulldown assays, used to search for
proteins capable to selectively bind tRF3E, have shown that this tRF specifically interacts with
nucleolin (NCL), an
RNA-binding protein overexpressed in BC and able to repress the translation of p53
mRNA. The binding properties of NCL-tRF3E complex, predicted in silico and analyzed by EMSA assays, are congruent with a competitive displacement of p53
mRNA by tRF3E, leading to an increased p53 expression and consequently to a modulation of
cancer cell growth. Here, we provide evidence that tRF3E plays an important role in the pathogenesis of BC displaying
tumor-suppressor functions through a NCL-mediated mechanism.-Falconi, M., Giangrossi, M., Elexpuru Zabaleta, M., Wang, J., Gambini, V., Tilio, M., Bencardino, D., Occhipinti, S., Belletti, B., Laudadio, E., Galeazzi, R., Marchini, C., Amici, A. A novel 3'-tRNAGlu-derived fragment acts as a
tumor suppressor in
breast cancer by targeting
nucleolin.