MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine

Oncotarget. 2015 Jun 10;6(16):14440-55. doi: 10.18632/oncotarget.3885.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with less than 5% of patients surviving 5 years beyond diagnosis. Systemic therapies, particularly gemcitabine, have a modest clinical benefit, but chemoresistance limits their efficacy. Here, we demonstrate that plasma miR-33a levels positively correlated with miR-33a levels in tumor tissues of patients with PDAC and are a good prognostic indicator of overall survival. Overexpression of miR-33a inhibited tumor cell proliferation and increased the chemosensitivity to gemcitabine both in vitro and in vivo. Moreover, miR-33a targets Pim-3 directly in PDAC. Pim-3 expression was a prognostic indicator related to poor survival in pancreatic cancer patients. Plasma miR-33a levels were significantly lower in pancreatic cancer patients with high Pim-3 protein expression than in healthy controls. Furthermore, overexpression of miR-33a in pancreatic cancer cell lines suppressed Pim-3 expression, leading to downregulation of the AKT/Gsk-3β/β-catenin pathway. Overall, these results indicate that miR-33a functions as a tumor suppressor that downregulates Pim-3 kinase expression to inhibit both pancreatic tumor growth and gemcitabine resistance via the AKT/β-catenin pathway. Hence, detection of plasma miR-33a may be a simple and convenient method of predicting therapeutic responses.

Keywords: chemoresistance; miR-33a; pancreatic cancer; serine/threonine kinase; tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / pathology
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Down-Regulation
  • Genes, Tumor Suppressor / drug effects*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction
  • Treatment Outcome

Substances

  • MicroRNAs
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Deoxycytidine
  • gemcitabine
  • PIM3 protein, human
  • Protein-Serine-Threonine Kinases