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

Mina Kalantari-Dehaghi1, Hans-Ulrich Bernard, Sergei A Grando

  • 1Department of Dermatology, University of California, Irvine, CA 92697, USA.

Life Sciences
|February 29, 2012
PubMed
Abstract

Insights

Tobacco nitrosamine (NNK) promotes cancer by altering gene expression in lung and oral cells. Secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1 (SLURP-1) reverses these effects, identifying key cancer-related genes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Tobacco nitrosamine (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK) is a potent carcinogen targeting bronchial and oral epithelial cells.
  • Nicotinic acetylcholine receptors (nAChRs) on these cells are implicated in NNK-induced carcinogenesis.
  • Secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1 (SLURP-1) can counteract NNK's effects.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which NNK facilitates carcinogenic transformation via nAChRs.
  • To identify specific genes targeted by NNK and SLURP-1 in bronchial and oral epithelial cells.
  • To understand the reciprocal effects of NNK and SLURP-1 on tumorigenesis.

Main Methods:

  • Comparison of gene expression profiles in human immortalized bronchial (BEP2D) and oral (Het-1A) epithelial cell lines.
  • Treatment with NNK and recombinant (r)SLURP-1 to assess their effects on oncogenic and tumor suppressor gene expression.
  • Analysis of changes in growth factors, transcription factors, and apoptosis-related genes.

Main Results:

  • NNK upregulated oncogenic genes (e.g., MYB, PIK3CA, ETS1, NRAS, SRC, AKT1, KIT, RB1) and growth factors (EGF, HGF), which were reversed by rSLURP-1.
  • NNK modulated apoptosis-related genes (BCL2, TNF, BAX, CASP8) and tumor suppressors (CDKN2A, STAT3, CDKN3, FOXD3, SERPINB5), with partial reversal by rSLURP-1.
  • NNK decreased β-catenin expression, an effect abolished by rSLURP-1, which also upregulated RUNX3.

Conclusions:

  • Identified specific target genes for NNK and SLURP-1 in bronchial and oral epithelial cells.
  • Elucidated the molecular mechanisms underlying the reciprocal effects of NNK and SLURP-1 on cellular tumorigenic transformation.
  • Provided insights into potential therapeutic targets for NNK-induced cancers.

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