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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, lu...

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Autores principales: Grabner, Beatrice, Schramek, Daniel, Mueller, Kristina M., Moll, Herwig P., Svinka, Jasmin, Hoffmann, Thomas, Bauer, Eva, Blaas, Leander, Hruschka, Natascha, Zboray, Katalin, Stiedl, Patricia, Nivarthi, Harini, Bogner, Edith, Gruber, Wolfgang, Mohr, Thomas, Zwick, Ralf Harun, Kenner, Lukas, Poli, Valeria, Aberger, Fritz, Stoiber, Dagmar, Egger, Gerda, Esterbauer, Harald, Zuber, Johannes, Moriggl, Richard, Eferl, Robert, Győrffy, Balázs, Penninger, Josef M., Popper, Helmut, Casanova, Emilio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366489/
https://www.ncbi.nlm.nih.gov/pubmed/25734337
http://dx.doi.org/10.1038/ncomms7285
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author Grabner, Beatrice
Schramek, Daniel
Mueller, Kristina M.
Moll, Herwig P.
Svinka, Jasmin
Hoffmann, Thomas
Bauer, Eva
Blaas, Leander
Hruschka, Natascha
Zboray, Katalin
Stiedl, Patricia
Nivarthi, Harini
Bogner, Edith
Gruber, Wolfgang
Mohr, Thomas
Zwick, Ralf Harun
Kenner, Lukas
Poli, Valeria
Aberger, Fritz
Stoiber, Dagmar
Egger, Gerda
Esterbauer, Harald
Zuber, Johannes
Moriggl, Richard
Eferl, Robert
Győrffy, Balázs
Penninger, Josef M.
Popper, Helmut
Casanova, Emilio
author_facet Grabner, Beatrice
Schramek, Daniel
Mueller, Kristina M.
Moll, Herwig P.
Svinka, Jasmin
Hoffmann, Thomas
Bauer, Eva
Blaas, Leander
Hruschka, Natascha
Zboray, Katalin
Stiedl, Patricia
Nivarthi, Harini
Bogner, Edith
Gruber, Wolfgang
Mohr, Thomas
Zwick, Ralf Harun
Kenner, Lukas
Poli, Valeria
Aberger, Fritz
Stoiber, Dagmar
Egger, Gerda
Esterbauer, Harald
Zuber, Johannes
Moriggl, Richard
Eferl, Robert
Győrffy, Balázs
Penninger, Josef M.
Popper, Helmut
Casanova, Emilio
author_sort Grabner, Beatrice
collection PubMed
description 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.
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spelling pubmed-43664892015-04-02 Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis Grabner, Beatrice Schramek, Daniel Mueller, Kristina M. Moll, Herwig P. Svinka, Jasmin Hoffmann, Thomas Bauer, Eva Blaas, Leander Hruschka, Natascha Zboray, Katalin Stiedl, Patricia Nivarthi, Harini Bogner, Edith Gruber, Wolfgang Mohr, Thomas Zwick, Ralf Harun Kenner, Lukas Poli, Valeria Aberger, Fritz Stoiber, Dagmar Egger, Gerda Esterbauer, Harald Zuber, Johannes Moriggl, Richard Eferl, Robert Győrffy, Balázs Penninger, Josef M. Popper, Helmut Casanova, Emilio Nat Commun Article 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. Nature Pub. Group 2015-03-03 /pmc/articles/PMC4366489/ /pubmed/25734337 http://dx.doi.org/10.1038/ncomms7285 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Grabner, Beatrice
Schramek, Daniel
Mueller, Kristina M.
Moll, Herwig P.
Svinka, Jasmin
Hoffmann, Thomas
Bauer, Eva
Blaas, Leander
Hruschka, Natascha
Zboray, Katalin
Stiedl, Patricia
Nivarthi, Harini
Bogner, Edith
Gruber, Wolfgang
Mohr, Thomas
Zwick, Ralf Harun
Kenner, Lukas
Poli, Valeria
Aberger, Fritz
Stoiber, Dagmar
Egger, Gerda
Esterbauer, Harald
Zuber, Johannes
Moriggl, Richard
Eferl, Robert
Győrffy, Balázs
Penninger, Josef M.
Popper, Helmut
Casanova, Emilio
Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
title Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
title_full Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
title_fullStr Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
title_full_unstemmed Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
title_short Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
title_sort disruption of stat3 signalling promotes kras-induced lung tumorigenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366489/
https://www.ncbi.nlm.nih.gov/pubmed/25734337
http://dx.doi.org/10.1038/ncomms7285
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