Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis.
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.
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria.
Beatrice
B
Grabner
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna 1030, Austria.
Daniel
D
Schramek
1] Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria [2] Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna 1210 and Medical University Vienna, Vienna 1090, Austria.
Kristina M
KM
Mueller
Institute of Pharmacology, Medical University of Vienna, Vienna 1090, Austria.
Herwig P
0000000164389068
HP
Moll
Institute of Cancer Research &Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
Jasmin
J
Svinka
Research Institute of Molecular Pathology (IMP), Dr. Bohr Gasse 7, Vienna 1030, Austria.
Thomas
T
Hoffmann
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria.
Eva
E
Bauer
Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Novum, Huddinge 141 83, Sweden.
Leander
L
Blaas
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria.
Natascha
N
Hruschka
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria.
Katalin
K
Zboray
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria.
Patricia
P
Stiedl
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria.
Harini
H
Nivarthi
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria.
Edith
E
Bogner
Department of Molecular Biology, Paris-Lodron University of Salzburg, Salzburg 5020, Austria.
Wolfgang
W
Gruber
Institute of Cancer Research &Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
Thomas
T
Mohr
Department of Internal Medicine, Karl Landsteiner University, 3430 Tulln, Austria.
Ralf Harun
RH
Zwick
1] Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria [2] Clinical Institute of Pathology, Medical University of Vienna, Vienna 1090, Austria [3] Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
Lukas
L
Kenner
Molecular Biotechnology Center (MBC), Department of Genetics, Biology and Biochemistry, University of Turin, Turin 10126, Italy.
Valeria
V
Poli
Department of Molecular Biology, Paris-Lodron University of Salzburg, Salzburg 5020, Austria.
Fritz
F
Aberger
1] Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria [2] Institute of Pharmacology, Medical University of Vienna, Vienna 1090, Austria.
Dagmar
D
Stoiber
Clinical Institute of Pathology, Medical University of Vienna, Vienna 1090, Austria.
Gerda
G
Egger
Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria.
Harald
H
Esterbauer
Research Institute of Molecular Pathology (IMP), Dr. Bohr Gasse 7, Vienna 1030, Austria.
Johannes
J
Zuber
1] Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria [2] Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna 1210 and Medical University Vienna, Vienna 1090, Austria.
Richard
0000000309189463
R
Moriggl
Institute of Cancer Research &Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
Robert
R
Eferl
1] MTA TTK Lendület Cancer Biomarker Research Group, Budapest 1117, Hungary [2] 2nd Department of Pediatrics, Semmelweis University, Budapest 1094, Hungary [3] MTA-SE Pediatrics and Nephrology Research Group, Budapest 1083, Hungary.
Balázs
B
Győrffy
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna 1030, Austria.
Josef M
JM
Penninger
Institute of Pathology, Research Unit Molecular Lung and Pleura Pathology, Medical University of Graz, Graz 8036, Austria.
Helmut
H
Popper
1] Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna 1090, Austria [2] Department of Physiology, Center of Physiology and Pharmacology, Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
Emilio
E
Casanova
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D046888:Tissue Array Analysis
D016209:Interleukin-8; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)