The oncogenic microRNA miR-21 promotes regulated necrosis in mice

Nat Commun. 2015 May 20;6:7151. doi: 10.1038/ncomms8151.

Abstract

MicroRNAs (miRNAs) regulate apoptosis, yet their role in regulated necrosis remains unknown. miR-21 is overexpressed in nearly all human cancer types and its role as an oncogene is suggested to largely depend on its anti-apoptotic action. Here we show that miR-21 is overexpressed in a murine model of acute pancreatitis, a pathologic condition involving RIP3-dependent regulated necrosis (necroptosis). Therefore, we investigate the role of miR-21 in acute pancreatitis injury and necroptosis. miR-21 deficiency protects against caerulein- or L-arginine-induced acute pancreatitis in mice. miR-21 inhibition using locked-nucleic-acid-modified oligonucleotide effectively reduces pancreatitis severity. miR-21 deletion is also protective in tumour necrosis factor-induced systemic inflammatory response syndrome. These data suggest that miRNAs are critical participants in necroptosis and miR-21 enhances cellular necrosis by negatively regulating tumour suppressor genes associated with the death-receptor-mediated intrinsic apoptosis pathway, and could be a therapeutic target for preventing pathologic necrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Arginine / genetics
  • Bone Marrow Transplantation
  • Caspases / metabolism
  • Ceruletide / genetics
  • Fas Ligand Protein / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor
  • Imidazoles / chemistry
  • Indoles / chemistry
  • Inflammation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • Necrosis*
  • Oligonucleotides / genetics
  • Pancreatitis / metabolism
  • RNA Interference
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • fas Receptor / metabolism

Substances

  • Fas Ligand Protein
  • Imidazoles
  • Indoles
  • MIRN21 microRNA, mouse
  • MicroRNAs
  • Oligonucleotides
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • necrostatin-1
  • Ceruletide
  • Arginine
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse
  • Caspases