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.
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.
Yang
Yongping
Y
Cell and Cancer Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Rockville, Maryland 20850, USA. yongpiny@mail.nih.gov
Zhang
Zhongjian
Z
Mukherjee
Anil B
AB
Linnoila
R Ilona
RI
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*
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