Aberrantly expressed miR-582-3p maintains lung cancer stem cell-like traits by activating Wnt/β-catenin signalling

Nat Commun. 2015 Oct 15;6:8640. doi: 10.1038/ncomms9640.

Abstract

Cancer stem cells (CSCs) are involved in tumorigenesis, tumour recurrence and therapy resistance and Wnt signalling is essential for the development of the biological traits of CSCs. In non-small cell lung carcinoma (NSCLC), unlike in colon cancer, mutations in β-catenin and APC genes are uncommon; thus, the mechanism underlying the constitutive activation of Wnt signalling in NSCLC remains unclear. Here we report that miR-582-3p expression correlates with the overall- and recurrence-free-survival of NSCLC patients, and miR-582-3p has an activating effect on Wnt/β-catenin signalling. miR-582-3p overexpression simultaneously targets multiple negative regulators of the Wnt/β-catenin pathway, namely, AXIN2, DKK3 and SFRP1. Consequently, miR-582-3p promotes CSC traits of NSCLC cells in vitro and tumorigenesis and tumour recurrence in vivo. Antagonizing miR-582-3p potently inhibits tumour initiation and progression in xenografted animal models. These findings suggest that miR-582-3p mediates the constitutive activation of Wnt/β-catenin signalling, likely serving as a potential therapeutic target for NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Axin Protein / metabolism
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Cell Line, Tumor
  • Chemokines
  • China / epidemiology
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / mortality
  • Male
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / metabolism*
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplasms, Experimental / metabolism
  • Neoplastic Stem Cells / physiology*
  • Phenotype
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism

Substances

  • AXIN2 protein, human
  • Adaptor Proteins, Signal Transducing
  • Axin Protein
  • Chemokines
  • DKK3 protein, human
  • Intercellular Signaling Peptides and Proteins
  • MIRN582 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • SFRP1 protein, human
  • Wnt Proteins
  • beta Catenin