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Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

Author

Listed:
  • Beatrice Grabner

    (Ludwig Boltzmann Institute for Cancer Research (LBI-CR))

  • Daniel Schramek

    (Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)
    Present addresses: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, Rockefeller University, 10065 New York, USA)

  • Kristina M. Mueller

    (Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
    Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna 1210 and Medical University Vienna)

  • 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)
    Present addresses: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria)

  • 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)
    Clinical Institute of Pathology, Medical University of Vienna
    Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna)

  • 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)
    Institute of Pharmacology, Medical University of Vienna)

  • 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)
    Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna 1210 and Medical University Vienna)

  • Robert Eferl

    (Comprehensive Cancer Center, Medical University of Vienna)

  • Balázs Győrffy

    (MTA TTK Lendület Cancer Biomarker Research Group
    Semmelweis University
    MTA-SE Pediatrics and Nephrology 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)
    Center of Physiology and Pharmacology, Comprehensive Cancer Center, Medical University of Vienna)

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.

Suggested Citation

  • 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 , 2015. "Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
  • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7285
    DOI: 10.1038/ncomms7285
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