Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis

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.

Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

“…Similarly, IL-6 and STAT3 are usually considered oncogenic proteins 24,44 but they have tumor suppressor properties in some contexts. 45 Consistent with this idea, short-term engraftment of CLL cells was enhanced by IL-6 in the absence of exogenous TLR signaling ( Figure 4B), suggesting a tumorpromoting effect of IL-6 in this model. However, TLR7 and TLR9 signaling are involved in the pathogenesis of progressive CLL.…”

The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism

“…6C). It has been shown that oncogenic KRAS-driven cancers require TBK1, which regulates BCL-XL expression (30) and cell survival involving autocrine IL-6, CCL5, and STAT3 signaling (31). In KRAS mutant HCT116 cells, however, we found that suppression of TBK1 by shRNA did not attenuate BCL-XL protein levels (Fig.…”

IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis

“…1A; refs. 7,40). By contrast, extensive AAH, diffuse AIS, and areas of invasive adenocarcinoma were observed throughout the lungs of gp130 F/F :Kras G12D mice, and there was an overall significant 2-fold increase in the area of lung parenchyma affected by these lesions in gp130 F/F :Kras G12D compared with Kras G12D mice ( Fig.…”

“…Although collectively these observations imply that STAT3 via IL6 trans-signaling can augment the oncogenic potential of mutant Kras in lung adenocarcinoma, recently it was reported that the lung epithelial-specific inactivation of Stat3 exacerbates Kras G12D -driven lung adenocarcinoma (40). The tumor-suppressive activity of STAT3 was assigned to its ability to sequester cytoplasmic NF-kB and inhibit NF-kB-induced transcription of the proangiogenic chemokine Cxcl1, thus suppressing tumor vascularization and growth.…”