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Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis.
- Source :
-
Nature communications [Nat Commun] 2015 Mar 03; Vol. 6, pp. 6285. Date of Electronic Publication: 2015 Mar 03. - Publication Year :
- 2015
-
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.
- Subjects :
- Adenocarcinoma genetics
Adenocarcinoma metabolism
Animals
Chromatin Immunoprecipitation
Enzyme-Linked Immunosorbent Assay
Gene Knockdown Techniques
Heterografts
Humans
Immunoblotting
In Situ Hybridization
Interleukin-8 metabolism
Lung Neoplasms genetics
Lung Neoplasms metabolism
Mice
NF-kappa B metabolism
Proto-Oncogene Proteins p21(ras) genetics
Real-Time Polymerase Chain Reaction
STAT3 Transcription Factor genetics
Statistics, Nonparametric
Tissue Array Analysis
Adenocarcinoma drug therapy
Carcinogenesis
Gene Expression Regulation, Neoplastic physiology
Lung Neoplasms drug therapy
Proto-Oncogene Proteins p21(ras) metabolism
STAT3 Transcription Factor metabolism
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 25734337
- Full Text :
- https://doi.org/10.1038/ncomms7285