title: The molecular features of tongue epithelium treated with the carcinogen 4-nitroquinoline-1-oxide and alcohol as a model for HNSCC.
abstract: Head and neck squamous cell carcinoma (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 (EtOH) for another 10 weeks. We observed increased levels and/or activation of signaling proteins [p38 mitogen-activated protein kinase (MAPK), β-catenin and Erk 1/2] that are typically altered during HNSCC initiation in humans. We found that EtOH administration alone increased the expression of p38 MAPK but not Erk 1/2 MAPK. Total β-catenin levels in the tongues increased by 2- to 3-fold after 4-NQO treatment, with or without EtOH. However, EtOH combined with 4-NQO reduced phosphorylated β-catenin levels, whereas 4-NQO treatment alone did not. These data implicate EtOH as a regulator of β-catenin signaling in this HNSCC model. We also utilized K14-CreER(TAM); ROSA26 mice to mark permanently stem/progenitor cells in the tongue epithelia. We found that 4-NQO alone and 4-NQO plus EtOH 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 MAPK and β-catenin.
authors.affiliation: Department of Pharmacology and.
authors.forename: Kwame
authors.initials: K
authors.lastname: Osei-Sarfo
authors.forename: Xiao-Han
authors.initials: XH
authors.lastname: Tang
authors.forename: Alison M
authors.initials: AM
authors.lastname: Urvalek
authors.forename: Theresa
authors.initials: T
authors.lastname: Scognamiglio
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D049109:Cell Proliferation; D002492:Central Nervous System Depressants / Q000633:toxicity; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006258:Head and Neck Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002273:Carcinogens; D002492:Central Nervous System Depressants; D051153:Wnt Proteins; D051176:beta Catenin; D000431:Ethanol; D015112:4-Nitroquinoline-1-oxide; D048051:p38 Mitogen-Activated Protein Kinases