Poster Presentation 26th Lorne Cancer Conference 2014

Interleukin (IL)-6 family cytokines signal exclusively via the gp130 co-receptor, and are implicated in smoking-associated lung cancer, the most lethal cancer worldwide. However, the role of gp130 signalling pathways in transducing the carcinogenic effects of tobacco-related compounds is ill-defined. Here, we report that lung tumourigenesis induced by the potent tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is suppressed in gp130^F/F knock-in mice characterized by the contrasting gp130-dependent hypo-activation of ERK/MAPK and PI3K/Akt, and hyper-activation of STAT3, signalling cascades. Specifically, in response to NNK, the absolute number and size of lung lesions in gp130^F/F mice were significantly reduced compared to gp130^+/+ littermate controls, and associated with lower cellular proliferation without any alteration to the level of apoptosis in gp130^F/F lung tumours. At the molecular level, reduced activation of ERK/MAPK, but not Akt, was observed in lung tumours of gp130^F/F mice, and corresponded with impaired expression of several tumour suppressor genes (e.g. Trp53, Tsc2). Notably, STAT3 was not activated in the lungs of gp130^+/+ mice by NNK, and genetic normalization of STAT3 activation in gp130^F/F:Stat3^-/+ mice had no effect on NNK-induced tumourigenesis. The expression of tumour suppressor genes was reduced in tumours from current versus never-smoking lung cancer patients, and in vitro pharmacological inhibition of ERK/MAPK signalling in human lung cancer cells abrogated NNK-induced down-modulation of tumour suppressor gene expression. Among IL-6 cytokine family members, IL-6 gene expression was specifically up-regulated by NNK in vitro and in vivo, and inversely correlated with tumour suppressor gene expression. Collectively, our data reveal that a key molecular mechanism by which NNK promotes tumour cell proliferation during tobacco carcinogen-induced lung carcinogenesis is via up-regulation of IL-6 and the preferential usage of gp130-dependent ERK/MAPK signalling to down-modulate tumour suppressor gene expression.