title: Reciprocal effects of NNK and SLURP-1 on oncogene expression in target epithelial cells.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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 β-catenin (BEP2D), as well as tumor suppressors CDKN3 and FOXD3 in BEP2D cells and SERPINB5 in Het-1A cells. These pro-oncogenic effects of NNK were abolished by rSLURP-1 that also upregulated RUNX3.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Dermatology, University of California, Irvine, CA 92697, USA.
authors.forename: Mina
authors.initials: M
authors.lastname: Kalantari-Dehaghi
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Bernard
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grando
mesh_terms: D000950:Antigens, Ly / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009055:Mouth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009602:Nitrosamines / Q000009:adverse effects* / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; D002273:Carcinogens; D009602:Nitrosamines; C048963:SLURP1 protein, human; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D014568:Urokinase-Type Plasminogen Activator