Chemical modifications in the seed region of miRNAs 221/222 increase the silencing performances in gastrointestinal stromal tumor cells

Montano Durso, Maria Gaglione, Linda Piras, Maria Emilia Mercurio, Sara Terreri, Michele Olivieri, Luciana Marinelli, Ettore Novellino, Mariarosaria Incoronato, Paolo Grieco, Gaetano Orsini, Giancarlo Tonon, Anna Messere, Amelia Cimmino

Research output: Contribution to journalArticlepeer-review

Abstract

Most GastroIntestinal Stromal Tumors (GISTs) are characterized by KIT gene overexpression, which in turn is regulated by levels of microRNA 221 and microRNA 222. GISTs can also be distinguished by their miRNAs expression profile in which miRNAs 221/222 result reduced in comparison with GI normal tissues. In this paper, to restore normal miRNAs levels and to improve the silencing performances of miRNAs 221/222, new miRNA mimics in which guide strands are modified by Phosphorothioate (PS) and/or 2′-O-methyl RNA (2′-OMe) inside and outside the seed region, were synthesized and tested in GIST48 cells. We evaluated the positional effect of the chemical modifications on the miRNAs silencing activity, compared to natural and several commercial miRNA mimics. Our results show that chemically modified miRNAs 221/222 with alternating 2′-OMe-PS and natural nucleotides in the seed region are effective inhibitors of KIT gene expression and exhibit increased stability in rat plasma. Besides, their transfection in GIST 48 cells showed significant effects on different cellular processes in which KIT plays a functional role for tumor development (such as migration, cell proliferation, and apoptosis). Therefore, modified miRNAs 221/222 may provide an alternative therapeutic option for GIST treatment also aimed to overcome drug resistance concerns.

Original languageEnglish
Pages (from-to)15-25
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume111
DOIs
Publication statusPublished - Mar 23 2016

Keywords

  • Chemically modified miR221/222
  • GIST treatment
  • Inhibitors of KIT gene expression
  • miRNA mimics
  • Therapeutic miRNAs

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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