Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

Nat Commun. 2015 Mar 3;6:6285. doi: 10.1038/ncomms7285.

Abstract

STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased Kras(G12D)-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-κB-induced IL-8 expression by sequestering NF-κB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3-NF-κB-IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Animals
  • Carcinogenesis*
  • Chromatin Immunoprecipitation
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation, Neoplastic / physiology*
  • Gene Knockdown Techniques
  • Heterografts
  • Humans
  • Immunoblotting
  • In Situ Hybridization
  • Interleukin-8 / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Real-Time Polymerase Chain Reaction
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / physiology*
  • Statistics, Nonparametric
  • Tissue Array Analysis

Substances

  • Interleukin-8
  • NF-kappa B
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)

Associated data

  • GEO/GSE52798