The rs17084733 variant in the KIT 3’ UTR disrupts a miR-221/222 binding site in gastrointestinal stromal tumour: a sponge-like mechanism conferring disease susceptibility

Riccardo Ricci, Gloria Ravegnini, César Serrano, Vittorio Simeon, Giulia Sammarini, Margherita Nannini, Erica Roversi, Milena Urbini, Fabrizio Ferrè, Giuseppe Tarantino, Maria A. Pantaleo, Patrizia Hrelia, Sabrina Angelini

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

5 Citazioni (Scopus)

Abstract

Several miRNAs are dysregulated in gastrointestinal stromal tumours (GIST), and miR-221/222 appear to have a prominent role in GIST biology. Therefore, we investigated the role of DNA variants located in miR-221/222 precursor sequences and their target KIT 3'UTR. Ninety-five polymorphisms were analysed in 115 GIST cases and 88 healthy controls. KIT 3'UTR rs17084733 and pri-miR-222 rs75246947 were found significantly associated with GIST susceptibility. Specifically, KIT rs17084733 A allele was more common in GIST, particularly in KIT wild-type (WT) patients (Padj = 0.017). rs17084733 variant is located within one of the three miR-221/222 binding sites in the KIT 3'UTR, resulting in a mismatch in this seed region. Conversely, KIT mRNA levels were lower in patients carrying the variant allele, except for KIT mutant GIST. Luciferase assay data in GIST cells, generated using a construct containing all the three miR-221/222 binding sites, are consistent with KIT mRNA levels in GIST patients. Reporter assay data, generated using a construct containing only the site encompassing rs17084733, confirmed that this is a functional variant disrupting the miR-221/222 binding site. In conclusion, this is the first study investigating the role of SNPs on miR-221/222 precursor sequences and their binding region on KIT 3'UTR in GIST. We identified the KIT variant rs17084733 as a possible novel genetic biomarker for risk of developing KIT-WT GIST. Moreover, our findings suggest the role of one of the three miR-221/222 binding sites on KIT 3'UTR as endogenous sponge, soaking up and subtracting miR-221/222 to the other two sites characterized by a higher affinity.
Lingua originaleEnglish
pagine (da-a)545-557
Numero di pagine13
RivistaEpigenetics
Volume14
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Cancer Research
  • GIST
  • KIT
  • Molecular Biology
  • SNP
  • epigenetics
  • gastrointestinal stromal tumor
  • imatinib
  • miR-221/222
  • miRNA sponge
  • miRSNP

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