title: Increased susceptibility of mice lacking Clara cell 10-kDa protein to lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen in cigarette smoke.
abstract: Ninety percent of all human lung cancers are related to cigarette smoking. Both tobacco smoke and lung tumorigenesis are associated with drastically reduced levels of Clara cell 10-kDa protein (CC10), a multifunctional secreted protein, naturally produced by the airway epithelia of virtually all mammals. We previously reported that the expression of CC10 is markedly reduced in animals exposed to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK, a potent carcinogen in tobacco smoke. Furthermore, it has been reported that CC10 expression, induced in certain tumor cells, reverses the transformed phenotype. We demonstrate here that NNK exposure of CC10-knock-out (CC10-KO) mice causes a significantly higher incidence of airway epithelial hyperplasia and lung adenomas compared with wild type (WT) littermates (30% CC10-KO versus 5% WT, p = 0.041). We also found that compared with NNK-treated WT mice, CC10-KO mice manifest increased frequency of K-ras mutation, elevated level of Fas ligand (FasL) expression, and increased MAPK/Erk phosphorylation, all of which are considered predisposing events in NNK-induced lung tumorigenesis. We propose that CC10 has a protective role against NNK-induced lung tumorigenesis mediated via down-regulation of the above-mentioned predisposing events.
authors.affiliation: Cell and Cancer Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Rockville, Maryland 20850, USA. yongpiny@mail.nih.gov
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Anil B
authors.initials: AB
authors.lastname: Mukherjee
authors.forename: R Ilona
authors.initials: RI
authors.lastname: Linnoila
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic; D004198:Disease Susceptibility; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D053222:Fas Ligand Protein; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009602:Nitrosamines / Q000494:pharmacology*; D012907:Smoking / Q000009:adverse effects*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D009602:Nitrosamines; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D014028:Tobacco Smoke Pollution; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D014598:Uteroglobin