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Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
VerfasserGrabner, 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 ; Zuber, Richard ; Moriggl, Richard
Erschienen in
Nature Communications, London, 2015, Jg. 6, S. 1-14
ErschienenNature Publishing Group, 2015
SpracheEnglisch
DokumenttypAufsatz in einer Zeitschrift
Schlagwörter (EN)Cancer therapy / Cell signalling / Lung cancer
Projekt-/ReportnummerP 25599
ISSN2041-1723
URNurn:nbn:at:at-ubs:3-3697 Persistent Identifier (URN)
DOI10.1038/ncomms7285 
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Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis [2.47 mb]
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Zusammenfassung (Englisch)

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-B-induced IL-8 expression by sequestering NF-B within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3NF-BIL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.

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CC-BY-Lizenz (4.0)Creative Commons Namensnennung 4.0 International Lizenz