Inflammation-driven carcinogenesis is mediated through STING

Nat Commun. 2014 Oct 10;5:5166. doi: 10.1038/ncomms6166.

Abstract

Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by mechanisms that are not well understood. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), cisplatin and etoposide induce nuclear DNA leakage into the cytosol that intrinsically activates stimulator of interferon genes (STING)-dependent cytokine production. Inflammatory cytokine levels are subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING(-/-) mice, or wild-type mice adoptively transferred with STING(-/-) bone marrow, are almost completely resistant to DMBA-induced skin carcinogenesis compared with their wild-type counterparts. Our data establish a role for STING in the control of cancer, shed significant insight into the causes of inflammation-driven carcinogenesis and may provide a basis for therapeutic strategies to help prevent malignant disease.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / immunology
  • Carcinogenesis / pathology
  • Cytokines / genetics
  • Cytokines / immunology
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / immunology
  • Female
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Knockout
  • Phosphoproteins / genetics
  • Phosphoproteins / immunology
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology

Substances

  • Cytokines
  • MPYS protein, mouse
  • Membrane Proteins
  • Phosphoproteins
  • 9,10-Dimethyl-1,2-benzanthracene
  • Exodeoxyribonucleases
  • three prime repair exonuclease 1

Associated data

  • GEO/GSE57605