title: Initiation of esophageal squamous cell carcinoma (ESCC) in a murine 4-nitroquinoline-1-oxide and alcohol carcinogenesis model.
abstract: Esophageal squamous cell carcinomas (ESCCs) are very common, aggressive tumors, and are often associated with alcohol and tobacco abuse. Because ESCCs exhibit high recurrence rates and are diagnosed at late stages, identification of prognostic and drug targets for prevention and treatment is critical. We used the 4-nitroquinoline-1-oxide (4-NQO) murine model of oral carcinogenesis and the Meadows-Cook model of alcohol abuse to assess changes in the expression of molecular markers during the initial stages of ESCC. Combining these two models, which mimic chronic alcohol and tobacco abuse in humans, we detected increased cellular proliferation (EGFR and Ki67 expression), increased canonical Wnt signaling and downstream elements (β-catenin, FoxM1, and S100a4 protein levels), changes in cellular adhesive properties (reduced E-cadherin in the basal layer of the esophageal epithelium), and increased levels of phosphorylated ERK1/2 and p38. Additionally, we found that treatment with ethanol alone increased the numbers of epithelial cells expressing solute carrier family 2 (facilitated glucose transporter, member 1) (SLC2A1) and carbonic anhydrase IX (CAIX), and increased the phosphorylation of p38. Thus, we identified both 4-NQO- and ethanol-specific targets in the initial stages of esophageal carcinogenesis, which should lead to the development of potential markers and therapeutic targets for human ESCC.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, USA.
authors.forename: Kwame
authors.initials: K
authors.lastname: Osei-Sarfo
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Urvalek
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, USA.
authors.forename: Xiao-Han
authors.initials: XH
authors.lastname: Tang
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Scognamiglio
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, USA.|The Meyer Cancer Center, Weill Cornell Medical College, New York, USA.
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D002273:Carcinogens; D000431:Ethanol; D015112:4-Nitroquinoline-1-oxide
keywords: 4-nitroquinoline-1-oxide; Meadows-Cook model of alcohol abuse; canonical and noncanonical Wnt signaling; cellular metabolism; esophageal squamous cell carcinoma