Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells

Teresa Bellissimo, Claudia Tito, Federica Ganci, Andrea Sacconi, Silvia Masciarelli, Giuseppe Di Martino, Natale Porta, Mirko Cirenza, Melissa Sorci, Luciana De Angelis, Paolo Rosa, Antonella Calogero, Alessandro Fatica, Vincenzo Petrozza, Giulia Fontemaggi, Giovanni Blandino, Francesco Fazi

Research output: Contribution to journalArticle

Abstract

To perform their regulatory functions, microRNAs (miRNAs) must assemble with any of the four mammalian Argonaute (Ago) family of proteins, Ago1–4, into an effector complex known as the RNA-induced silencing complex (RISC). While the mature miRNA guides the RISC complex to its target mRNA, the Ago protein represses mRNA translation. The specific roles of the various Ago members in mediating miRNAs activity, however, haven’t been clearly established. In this study, we investigated the contribution of Ago2, the only human Ago protein endowed with nuclease activity, to the function of tumor-suppressor miR-145-5p in breast cancer (BC). We show that miR-145-5p and Ago2 protein are concomitantly downregulated in BC tissues and that restoration of miR-145-5p expression in BC cells leads to Ago2 protein induction through the loosening of Ago2 mRNA translational repression. Functionally, miR-145-5p exerts its inhibitory activity on cell migration only in presence of Ago2, while, upon Ago2 depletion, we observed increased miR-145/Ago1 complex and enhanced cell motility. Profiling by microarray of miR-145-5p target mRNAs, in BC cells depleted or not of Ago2, revealed that miR-145-5p drives Ago2-dependent and -independent activities. Our results highlight that the Ago2 protein in cancer cells strictly dictates miR-145-5p tumor suppressor activity.

Original languageEnglish
Article number17
JournalCell Death and Disease
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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  • Cite this

    Bellissimo, T., Tito, C., Ganci, F., Sacconi, A., Masciarelli, S., Di Martino, G., Porta, N., Cirenza, M., Sorci, M., De Angelis, L., Rosa, P., Calogero, A., Fatica, A., Petrozza, V., Fontemaggi, G., Blandino, G., & Fazi, F. (2019). Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells. Cell Death and Disease, 10(1), [17]. https://doi.org/10.1038/s41419-018-1267-5