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Type of publication: Journal Article
Type of document: Full Paper

Year: 2015

Authors: Grabner, B; Schramek, D; Mueller, KM; Moll, HP; Svinka, J; Hoffmann, T; Bauer, E; Blaas, L; Hruschka, N; Zboray, K; Stiedl, P; Nivarthi, H; Bogner, E; Gruber, W; Mohr, T; Zwick, RH; Kenner, L; Poli, V; Aberger, F; Stoiber, D; Egger, G; Esterbauer, H; Zuber, J; Moriggl, R; Eferl, R; Győrffy, B; Penninger, JM; Popper, H; Casanova, E

Title: Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis.

Source: Nat Commun. 2015; 6:6285



Authors Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard
Müller Kristina

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


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.

Keywords Pubmed: 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


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