MicroRNA-29a induces resistance to gemcitabine through the Wnt/β-catenin signaling pathway in pancreatic cancer cells

Int J Oncol. 2013 Oct;43(4):1066-72. doi: 10.3892/ijo.2013.2037. Epub 2013 Jul 24.

Abstract

Although we studied previously the mechanisms of resistance of pancreatic cancer cells to gemcitabine (GEM), prediction of the response to GEM remains unsatisfactory. The aim of this study was to investigate the relationship between miR-29a expression and the response to GEM in pancreatic cancer cells. Changes in the growth-inhibitory effect of pancreatic cancer cells (MIAPaCa-2, PSN-1, BxPC-3 and Panc-1) to GEM were examined after overexpression or suppression of miR-29a. We also examined the effect of miR-29a on the Wnt/β-catenin signaling pathway and investigated whether the altered growth-inhibitory effect by miR-29a suppression was weakened after the addition of Wnt3a, a Wnt/β-catenin signaling activator. MIAPaCa-2 and PSN-1 cells transfected with anti-miR-29a showed significantly lower resistance to GEM. In the anti-miR-29a-transfected cells, GEM induced significantly larger numbers of apoptotic cells and S phase accumulation compared to control cells, demonstrated by Annexin V assay and flow cytometric analysis of the cell cycle, respectively. The transfected cells showed overexpression of putative target molecules including Dkk1, Kremen2 and sFRP2 and lower activation of the Wnt/β-catenin signaling pathway. The addition of Wnt3a weakened the augmented growth-inhibitory effect of anti-miR-29a transfection. Our findings suggest that miR-29a expression correlates significantly with the growth-inhibitory effect of GEM and that activation of the Wnt/β-catenin signaling pathway mediated the miR-29a-induced resistance to GEM in pancreatic cancer cell lines.

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Drug Resistance, Neoplasm / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Signal Transduction / drug effects
  • Wnt Signaling Pathway / drug effects
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • MIRN29a microRNA, human
  • MicroRNAs
  • beta Catenin
  • Deoxycytidine
  • gemcitabine