Reciprocal effects of NNK and SLURP-1 on oncogene expression in target epithelial cells

[摘要] Aims: To elucidate how the nicotinic acetylcholine receptors expressed on bronchial and oral epithelial cells targeted by the tobacco nitrosamine (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK) facilitate carcinogenic transformation. Main methods: Since NNK-dependent transformation can be abolished by the nicotinergic secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1 (SLURP-1), we compared effects of NNK and recombinant (r)SLURP-1 on the expression of genes related to tumorigenesis in human immortalized bronchial and oral epithelial cell lines BEP2D and Het-1A, respectively. Key findings: NNK stimulated expression of oncogenic genes, including MYB and PIK3CA in BEP2D, ETS1, NRAS and SRC in Het-1A, and AKT1, KIT and RB1 in both cell types, which could be abolished in the presence of rSLURP-1. Other cancer-related genes whose upregulation by NNK was abolishable by rSLURP-1 were the growth factors EGF in BEP2D cells and HGF in Het-1A cells, and the transcription factors CDKN2A and STAT3 (Het-1A only). NNK also upregulated the anti-apoptotic BCL2 (Het-1A) and downregulated the pro-apoptotic TNF (Het-1A), BAX and CASP8 (BEP2D), all of which could be abolished, in part, by rSLURP-1. NNK decreased expression of the CTNNB1 gene encoding the intercellular adhesion molecule beta-catenin (BEP2D), as well as tumor suppressors CDKN3 and FOXD3 in BEP2D cells and SERPINBS in Het-1A cells. These pro-oncogenic effects of NNK were abolished by rSLURP-1 that also upregulated RUNX3. Significance: The obtained results identified target genes for both NNK and SLURP-1 and shed light on the molecular mechanism of their reciprocal effects on tumorigenic transformation of bronchial and oral epithelial cells. (C) 2012 Elsevier Inc. All rights reserved.

[发布日期] 2012-11-27

[效力级别]  Proceedings Paper

[关键词] Lung cancer;Head and neck cancers;NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone);SLURP-1 (secreted mammalian Ly-6/urokinase;plasminogen activator receptor related protein-1);Gene expression;BEP2D cells;Het-1A cells