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Nature Research, Nature Communications, 1(6), 2015

DOI: 10.1038/ncomms7285

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Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

Journal article published in 2015 by Beatrice Grabner, Daniel Schramek ORCID, Kristina M. Mueller, Herwig P. Moll ORCID, Jasmin Svinka, Thomas Hoffmann, Eva Bauer, Leander Blaas ORCID, Natascha Hruschka, Katalin Zboray, Patricia Stiedl, Harini Nivarthi, Edith Bogner, Wolfgang Gruber, Thomas Mohr and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractSTAT3 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.