Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

Beatrice Grabner, Daniel Schramek, Kristina M. Mueller, Herwig P. Moll, Jasmin Svinka, Thomas Hoffmann, Eva Bauer, Leander Blaas, Natascha Hruschka, Katalin Zboray, Patricia Stiedl, Harini Nivarthi, Edith Bogner, Wolfgang Gruber, Thomas Mohr, Ralf Harun Zwick, Lukas Kenner, Valeria Poli, Fritz Aberger, Dagmar Stoiber, Gerda Egger, Harald Esterbauer, Johannes Zuber, Richard Moriggl, Robert Eferl, Balázs Győrffy, Josef M. Penninger, Helmut Popper and Emilio Casanova ()
Additional contact information
Beatrice Grabner: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Daniel Schramek: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Kristina M. Mueller: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Herwig P. Moll: Institute of Pharmacology, Medical University of Vienna
Jasmin Svinka: Comprehensive Cancer Center, Medical University of Vienna
Thomas Hoffmann: Research Institute of Molecular Pathology (IMP), Dr. Bohr Gasse 7
Eva Bauer: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Leander Blaas: Center for Innovative Medicine, Karolinska Institutet
Natascha Hruschka: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Katalin Zboray: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Patricia Stiedl: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Harini Nivarthi: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Edith Bogner: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Wolfgang Gruber: Paris-Lodron University of Salzburg
Thomas Mohr: Comprehensive Cancer Center, Medical University of Vienna
Ralf Harun Zwick: Karl Landsteiner University
Lukas Kenner: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Valeria Poli: Molecular Biotechnology Center (MBC), Biology and Biochemistry, University of Turin
Fritz Aberger: Paris-Lodron University of Salzburg
Dagmar Stoiber: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Gerda Egger: Clinical Institute of Pathology, Medical University of Vienna
Harald Esterbauer: Medical University of Vienna
Johannes Zuber: Research Institute of Molecular Pathology (IMP), Dr. Bohr Gasse 7
Richard Moriggl: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
Robert Eferl: Comprehensive Cancer Center, Medical University of Vienna
Balázs Győrffy: MTA TTK Lendület Cancer Biomarker Research Group
Josef M. Penninger: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
Helmut Popper: Institute of Pathology, Research Unit Molecular Lung and Pleura Pathology, Medical University of Graz
Emilio Casanova: Ludwig Boltzmann Institute for Cancer Research (LBI-CR)

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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 KrasG12D-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.

Date: 2015
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DOI: 10.1038/ncomms7285

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