title: Differential involvement of gp130 signalling pathways in modulating tobacco carcinogen-induced lung tumourigenesis.
abstract: 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.
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Miller
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia.
authors.forename: G D
authors.initials: GD
authors.lastname: Brooks
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: McLeod
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Ruwanpura
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, Australia.
authors.forename: B J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009602:Nitrosamines / Q000009:adverse effects* / Q000378:metabolism
chemical_list: D002273:Carcinogens; C508600:IL6 protein, human; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D009602:Nitrosamines; C577686:interleukin-6, mouse; D050822:Cytokine Receptor gp130; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
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