The over-expression of miR-34a fails to block DoHH2 lymphoma cell proliferation by reducing p53 via c-MYC down-regulation

Nucleic Acid Ther. 2012 Aug;22(4):283-8. doi: 10.1089/nat.2012.0343. Epub 2012 Jul 25.

Abstract

MicroRNAs (miRNAs) might behave as tumor suppressors and for that they are under consideration as novel therapeutic drugs. We tested the tumor suppressor activity of miRNA-34a (miR-34a) by measuring cell proliferation of the follicular lymphoma cell line DoHH2 transfected with this miRNA. We report that miR-34a did not inhibit cell proliferation notwithstanding a marked down-regulation of c-MYC. Interestingly, DoHH2 transfected cells showed a significant p53 down-regulation, suggesting that c-MYC positively controls p53 and the failed inhibition of cell proliferation is probably due to the down-regulation of the c-MYC/p53 axis. In keeping with this, c-MYC silencing also down-regulated p53 and had no effect on cell proliferation. In accordance with this hypothesis, etoposide or nutlin-3 treatment or a small interfering RNA (siRNA) against BCL6 (B-cell lymphoma 6) inhibited the proliferation of DoHH2 cells by up-regulating p53 without affecting either miR-34a or c-MYC levels. These results indicate that the proliferation is controlled by the regulatory axis c-MYC/p53 and suggest that paradoxically miR-34a behaves as a pro-proliferative rather than an anti-proliferative miRNA in DoHH2 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation*
  • DNA-Binding Proteins / metabolism
  • Down-Regulation*
  • Etoposide / pharmacology
  • Gene Expression
  • Green Fluorescent Proteins / biosynthesis
  • Green Fluorescent Proteins / genetics
  • Humans
  • Imidazoles / pharmacology
  • Lymphoma
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference*
  • Transfection
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • 3' Untranslated Regions
  • Antineoplastic Agents, Phytogenic
  • BCL6 protein, human
  • DNA-Binding Proteins
  • Imidazoles
  • MIRN34 microRNA, human
  • MYC protein, human
  • MicroRNAs
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-6
  • Proto-Oncogene Proteins c-myc
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • nutlin 3
  • Etoposide