A novel 3'-tRNAGlu-derived fragment acts as a tumor suppressor in breast cancer by targeting nucleolin

Maurizio Falconi, Mara Giangrossi, Maria Elexpuru Zabaleta, Junbiao Wang, Valentina Gambini, Martina Tilio, Daniela Bencardino, Sergio Occhipinti, Barbara Belletti, Emiliano Laudadio, Roberta Galeazzi, Cristina Marchini, Augusto Amici

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)13228-13240
Number of pages13
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number12
DOIs
Publication statusPublished - Dec 1 2019

Keywords

  • HER2
  • p53 protein
  • RNA-protein interaction
  • small noncoding RNAs

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'A novel 3'-tRNA<sup>Glu</sup>-derived fragment acts as a tumor suppressor in breast cancer by targeting nucleolin'. Together they form a unique fingerprint.

Cite this