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Carcinogenesis Advance Access originally published online on March 16, 2006
Carcinogenesis 2006 27(7):1489-1496; doi:10.1093/carcin/bgl012
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Louise Y.Y. Fong 1, *, Yubao Jiang 2 and John L. Farber 2

Department of Molecular Virology, Immunology and Medical Genetics 1 Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA and 2 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA

* To whom correspondence should be addressed at: Comprehensive Cancer Center, Ohio State University, Room 388A, Tzagournis Medical Research Facility, 420 W. 12th Avenue, Columbus, OH 43210, USA. Tel: +1 614 688 5914; Fax: +1 614 688 4020; Email: Louise.Fong{at}osumc.edu

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.


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