Journal Article

Zinc deficiency potentiates induction and progression of lingual and esophageal tumors in p53-deficient mice

Louise Y.Y. Fong, Yubao Jiang and John L. Farber

in Carcinogenesis

Volume 27, issue 7, pages 1489-1496
Published in print July 2006 | ISSN: 0143-3334
Published online March 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl012
Zinc deficiency potentiates induction and progression of lingual and esophageal tumors in p53-deficient mice

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Upper aerodigestive tract (UADT) cancer, including oral and esophageal cancer, is an important cause of cancer deaths worldwide. Patients with UADT cancer are frequently zinc deficient (ZD) and show a loss of function of the pivotal tumor suppressor gene p53. The present study examined whether zinc deficiency in collaboration with p53 insufficiency (p53+/−) promotes lingual and esophageal tumorigenesis in mice exposed to low doses of the carcinogen 4-nitroquinoline 1-oxide. In wild-type mice, ZD significantly increased the incidence of lingual and esophageal tumors from 0% in zinc sufficient (ZS) ZS:p53+/+ mice to ∼40%. On the p53+/− background, ZD:p53+/− mice had significantly greater tumor incidence and multiplicity than ZS:p53+/− and ZD:p53+/+ mice, with a high frequency of progression to malignancy. Sixty-nine and 31% of ZD:p53+/− lingual and esophageal tumors, respectively, were squamous cell carcinoma versus 19 and 0% of ZS:p53+/− tumors (tongue, P = 0.003; esophagus, P = 0.005). Immunohistochemical analysis revealed that the increased cellular proliferation observed in preneoplastic lingual and esophageal lesions, as well as invasive carcinomas, was accompanied by overexpression of cytokeratin 14, cyclooxygenase-2 and metallothionein. In summary, a new UADT cancer model is developed in ZD:p53+/− mouse that recapitulates aspects of the human cancer and provides opportunities to probe the genetic changes intrinsic to UADT carcinogenesis and to test strategies for prevention and reversal of this deadly cancer.

Keywords: COX, cyclooxygenase; DAB, 3,3′-diaminobenzidine tetrahydrochloride; H&E, hematoxylin and eosin; KRT14, keratin 14; MT, metallothionein; NQO, 4-nitroquinoline 1-oxide; NMBA, N-nitrosomethylbenzylamine; PCNA, proliferating cell nuclear antigen; SCC, squamous cell carcinoma; UADT, upper aerodigestive tract; ZD, zinc deficient; ZS, zinc sufficient

Journal Article.  5282 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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