EGCG Disrupts the LIN28B/Let-7 Interaction and Reduces Neuroblastoma Aggressiveness

Author:

Cocchi Simona1,Greco Valentina1,Sidarovich Viktoryia1,Vigna Jacopo12ORCID,Broso Francesca1ORCID,Corallo Diana3,Zasso Jacopo1ORCID,Re Angela1,Rosatti Emanuele Filiberto1ORCID,Longhi Sara1ORCID,Defant Andrea2ORCID,Ladu Federico4,Sanna Vanna5ORCID,Adami Valentina1,D’Agostino Vito G.1ORCID,Sturlese Mattia6ORCID,Sechi Mario4ORCID,Aveic Sanja3ORCID,Mancini Ines2ORCID,Sighel Denise1ORCID,Quattrone Alessandro1

Affiliation:

1. Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy

2. Department of Physics, University of Trento, 38123 Trento, Italy

3. Istituto di Ricerca Pediatrica Fondazione Città della Speranza, 35127 Padova, Italy

4. Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100 Sassari, Italy

5. Nanomater S.r.l., 07041 Alghero, Italy

6. Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35127 Padova, Italy

Abstract

Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (−)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation.

Funder

Associazione Italiana per la Ricerca sul Cancro

a donation from Enrico and Ivana Zobele

Associazione Italiana per la Lotta al Neuroblastoma ONLUS

Publisher

MDPI AG

Reference77 articles.

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