2. Academic Validation
  3. OncomiRs miR-106a and miR-17 negatively regulate the nucleoside-derived drug transporter hCNT1

OncomiRs miR-106a and miR-17 negatively regulate the nucleoside-derived drug transporter hCNT1

  • Cell Mol Life Sci. 2021 Dec;78(23):7505-7518. doi: 10.1007/s00018-021-03959-8.
Clara Boces-Pascual 1 2 3,  Aida Mata-Ventosa 1 2 3,  Mireia Martín-Satué 4 5 6,  Loreto Boix 2 7,  Meritxell Gironella 2 8,  Marçal Pastor-Anglada 1 2 3,  Sandra Pérez-Torras 9 10 11
Affiliations

Affiliations

  • 1 Molecular Pharmacology and Experimental Therapeutics, Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain.
  • 2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain.
  • 3 Institut de Recerca Sant Joan de Déu (IR SJD-CERCA), Esplugues de Llobregat, Barcelona, Spain.
  • 4 Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Campus of Bellvitge, University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain.
  • 5 Biomedical Research Institute of Bellvitge (IDIBELL), Oncobell Program, L'Hospitalet de Llobregat, Barcelona, Spain.
  • 6 Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
  • 7 Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Fundació Clínic per a la Recerca Biomèdica (FCRB), University of Barcelona, Barcelona, Spain.
  • 8 Gastrointestinal & Pancreatic Oncology Group, Hospital Clinic of Barcelona/Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • 9 Molecular Pharmacology and Experimental Therapeutics, Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona (IBUB), Barcelona, Spain. s.perez-torras@ub.edu.
  • 10 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain. s.perez-torras@ub.edu.
  • 11 Institut de Recerca Sant Joan de Déu (IR SJD-CERCA), Esplugues de Llobregat, Barcelona, Spain. s.perez-torras@ub.edu.
PMID: 34647142 DOI: 10.1007/s00018-021-03959-8
Abstract

High-affinity uptake of natural nucleosides as well as nucleoside derivatives used in Anticancer therapies is mediated by human concentrative nucleoside transporters (hCNTs). hCNT1, the hCNT family member that specifically transports pyrimidines, is also a transceptor involved in tumor progression. In particular, oncogenesis appears to be associated with hCNT1 downregulation in some cancers, although the underlying mechanisms are largely unknown. Here, we sought to address changes in colorectal and pancreatic ductal adenocarcinoma-both of which are important digestive cancers-in the context of treatment with fluoropyrimidine derivatives. An analysis of Cancer samples and matching non-tumoral adjacent tissues revealed downregulation of hCNT1 protein in both types of tumor. Further exploration of the putative regulation of hCNT1 by MicroRNAs (miRNAs), which are highly deregulated in these cancers, revealed a direct relationship between the oncomiRs miR-106a and miR-17 and the loss of hCNT1. Collectively, our findings provide the first demonstration that hCNT1 inhibition by these oncomiRs could contribute to chemoresistance to fluoropyrimidine-based treatments in colorectal and pancreatic Cancer.

Keywords

CNT1; Chemoresistance; Non-coding RNA; Nucleoside analog; Nucleoside transporter.

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