Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

作者：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; Gyorffy Balazs; Penninger Josef M; Popper Helmut; Casanova Emilio^*

来源：Nature Communications, 2015, 6(1): 6285.

DOI：10.1038/ncomms7285

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-kappa B-induced IL-8 expression by sequestering NF-kappa B 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-kappa B-IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.

• 出版日期2015-3