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Wednesday, June 26, 2013

The molecular features of tongue epithelium treated with the carcinogen 4-nitroquinoline-1-oxide (4-NQO) and alcohol as a model for HNSCC.

Cancer of the head and neck (HNSCC) is the sixth most common type of cancer affecting humans worldwide. To determine the potential mechanisms by which chronic tobacco and alcohol abuse lead to HNSCC of the oral cavity, we have used both the 4-nitroquinoline-1-oxide (4-NQO) murine oral carcinogenesis and the Meadows-Cook alcohol models.

In this study, we treated mice with 4-NQO in drinking water for 10 weeks and then administered 20%(w:v) ethanol for another 10 weeks. We observe increased levels and/or activation of signaling proteins (p38 MAP kinase, β-catenin, and Erk 1/2) that are typically altered during HNSCC initiation in humans.

We found that ethanol administration alone increased the expression of p38 MAP kinase, but not Erk 1/2 MAP kinase. Total β-catenin levels in the tongues increased by 2-3 fold after 4-NQO treatment, with or without ethanol. However, ethanol combined with 4-NQO reduced phosphorylated β-catenin levels, whereas 4-NQO treatment alone did not.

These data implicate ethanol as a regulator of β-catenin signaling in this HNSCC model. We also utilized K14-CreERTAM;ROSA26 mice to mark permanently stem/progenitor cells in the tongue epithelia.

We found that 4-NQO alone and 4-NQO plus ethanol treatment resulted in massive, horizontal expansion of stem/progenitor cell populations arising from single stem cells in the basal layer of the epithelia. This expansion is consistent with carcinogen associated, symmetric division of stem/progenitor cells.

Our data suggest that specific therapeutic targets for prevention of HNSCC of the oral cavity associated with both alcohol and tobacco use are p38 MAP kinase and β-catenin.

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