Dietary Zinc Modulation of COX-2 Expression and Lingual and Esophageal Carcinogenesis in Rats

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Abstract
Background: Cancer of the upper aerodigestive tract, including esophageal and tongue carcinomas, is a major cause of cancer deaths worldwide. Esophageal and tongue cancers have both been associated with dietary zinc deficiency (ZD), and cyclooxygenase (COX-2) is often overexpressed in these cancers. Using rat models, we examined whether zinc regulates COX-2 expression in these cancers. Method: Expression of COX-2 protein and mRNA in rat lingual and esophageal epithelia in control (zinc sufficient [ZS]) rats, during ZD, and after intragastric zinc replenishment (ZR) were determined by immunoblotting, immunohistochemistry, and real-time quantitative polymerase chain reaction. COX-2 gene expression, cell proliferation, and apoptosis were analyzed in ZD, ZR, and ZD rats treated with the COX-2 inhibitors celecoxib and indomethacin. Tumor development in ZD rats treated by continuous exposure to the carcinogen 4-nitroquinoline 1 oxide (NQO), which causes tongue tumors in rats, was compared with those in NQO-treated ZS rats. Statistical tests were two-sided. Results: The esophagus and tongue of ZD rats were hyperplastic and expressed COX-2 protein and mRNA at 8- to 14.7-fold higher levels than control rats. Within hours ZR reduced COX-2 overexpression to threefold that in control rats and reversed the hyperplastic phenotypes. The esophagus of ZD rats treated with celecoxib or indomethacin showed a reduction in cell proliferation and stimulation of apoptosis. NQO treatment resulted in greater incidence of lingual squamous cell carcinomas (74% versus 22%, difference = 52%, 95% confidence interval [CI] = 20% to 80%, P = .015) and greater tumor multiplicity (13.1 versus 4.3, difference = 8.8, 95% CI = 7.0 to 10.6, P = .018) in ZD than ZS rats. Of 23 NQO-treated ZD rats, 39% (9) and 61% (14) harbored esophageal and forestomach tumors, respectively, whereas none of the NQO-treated ZS rats did. Conclusions: COX-2 overexpression accompanies hyperplasia in ZD rats. Increased cell proliferation in NQO-treated ZD rats facilitates the development of tumors at multiple sites. The finding that zinc regulates COX-2 expression in vivo in an animal model may lead to prevention or therapeutic possibilities for upper aerodigestive tract cancer.