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Interleukin (IL)-6 family cytokines signal exclusively via the gp130 coreceptor, 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 (Nicotine-derived Nitrosamine Ketone; NNK) is suppressed in gp130 F/F knock-in mice characterized by the contrasting gp130-dependant hypoactivation of extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) and phosphatidylinositol 3-kinase/Akt, and hyperactivation of signal transducer and activator of transcription (STAT)3 signalling cascades. Specifically, in response to NNK, the absolute number and size of lung lesions in gp130 F/F mice were significantly reduced compared with 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 (for example, 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 downmodulation of tumour suppressor gene expression. Among IL-6 cytokine family members, IL-6 gene expression was specifically upregulated 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 upregulation of IL-6 and the preferential usage of gp130-dependant ERK MAPK signalling to downmodulate tumour suppressor gene expression.
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