TY - JOUR
T1 - Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
AU - Grabner, Beatrice
AU - Schramek, Daniel
AU - Mueller, Kristina M
AU - Moll, Herwig P
AU - Svinka, Jasmin
AU - Hoffmann, Thomas
AU - Bauer, Eva
AU - Blaas, Leander
AU - Hruschka, Natascha
AU - Zboray, Katalin
AU - Stiedl, Patricia
AU - Nivarthi, Harini
AU - Bogner, Edith
AU - Gruber, Wolfgang
AU - Mohr, Thomas
AU - Zwick, Ralf Harun
AU - Kenner, Lukas
AU - Poli, Valeria
AU - Aberger, Fritz
AU - Stoiber, Dagmar
AU - Egger, Gerda
AU - Esterbauer, Harald
AU - Zuber, Johannes
AU - Moriggl, Richard
AU - Eferl, Robert
AU - Győrffy, Balázs
AU - Penninger, Josef M
AU - Popper, Helmut
AU - Casanova, Emilio
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/3/4
Y1 - 2015/3/4
N2 - 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.
AB - 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.
KW - Adenocarcinoma/drug therapy
KW - Animals
KW - Carcinogenesis
KW - Chromatin Immunoprecipitation
KW - Enzyme-Linked Immunosorbent Assay
KW - Gene Expression Regulation, Neoplastic/physiology
KW - Gene Knockdown Techniques
KW - Heterografts
KW - Humans
KW - Immunoblotting
KW - In Situ Hybridization
KW - Interleukin-8/metabolism
KW - Lung Neoplasms/drug therapy
KW - Mice
KW - NF-kappa B/metabolism
KW - Proto-Oncogene Proteins p21(ras)/genetics
KW - Real-Time Polymerase Chain Reaction
KW - STAT3 Transcription Factor/genetics
KW - Signal Transduction/physiology
KW - Statistics, Nonparametric
KW - Tissue Array Analysis
UR - http://www.scopus.com/inward/record.url?scp=84924185168&partnerID=8YFLogxK
U2 - 10.1038/ncomms7285
DO - 10.1038/ncomms7285
M3 - Journal article
C2 - 25734337
SN - 2041-1723
VL - 6
SP - 6285
JO - Nature Communications
JF - Nature Communications
M1 - 6285
ER -