In this study, we used the gp130(F/F) (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis.
Collectively, our data reveal that a key molecular mechanism by which NNK promotes tumour cell proliferation during tobacco carcinogen-induced lung carcinogenesis is via upregulation of IL-6 and the preferential usage of gp130-dependant ERK MAPK signalling to downmodulate tumour suppressor gene expression.
Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis.
Specific targeting of stomach epithelial STAT3 or blocking IL-11Rα/gp130 and/or EGFR signal transduction in chronic gastric inflammation and metaplasia may be therapeutically effective in preventing gastric carcinogenesis.
Surprisingly, the genetic reduction of STAT1 expression also reduced gastric tumorigenesis in gp130(Y757F/Y757F) mice and coincided with reduced gastric inflammation and IL-11 expression.