MicroRNA-365a-3p inhibits c-Rel-mediated NF-κB signaling and the progression of pancreatic cancer

Cancer Lett. 2019 Jun 28:452:203-212. doi: 10.1016/j.canlet.2019.03.025. Epub 2019 Mar 23.

Abstract

NF-κB contributes to the aggressiveness of pancreatic ductal adenocarcinoma (PDA), which is counteracted by the bioactive agent sulforaphane. We investigated sulforaphane-induced microRNA signaling and its influence on progression features. Using established cell lines, microRNA and gene arrays, we predicted miR-365a as the top candidate for the sulforaphane-induced inhibition of the NF-κB subunit c-Rel. The lipofection of miR-365a-3p mimics inhibited the luciferase activity of a c-Rel 3'-UTR construct, as well as c-Rel expression, NF-κB activity, and tumor viability, migration, and clonogenicity, whereas apoptosis was induced. In vivo, miR-365a-3p reduced the volume of tumor xenografts and the expression of progression markers. In a tissue array, the expression of miR-365a-3p was absent in almost all 91 malignant tissues but not in 5 normal tissues, thus confirming the previous results. Our observations suggest that sulforaphane-induced miR-365a-3p expression inhibits NF-κB activity by downregulating c-Rel, which prevents the progression of PDA.

Keywords: NF-κB signaling; Pancreatic cancer; Sulforaphane; microRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chick Embryo
  • Disease Progression
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Isothiocyanates / pharmacology
  • MicroRNAs / drug effects
  • MicroRNAs / genetics*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins c-rel / metabolism*
  • Signal Transduction
  • Sulfoxides
  • Transcription Factor RelA / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Anticarcinogenic Agents
  • Isothiocyanates
  • MIRN365 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-rel
  • REL protein, human
  • RELA protein, human
  • Sulfoxides
  • Transcription Factor RelA
  • sulforaphane