Dietary zinc modulation of COX-2 expression and lingual and esophageal carcinogenesis in rats.
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.


METHODS
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.
Fong
Louise Y Y
LY
Kimmel Cancer Center, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107. louise.fong@jefferson.edu.
Zhang
Liang
L
Jiang
Yubao
Y
Farber
John L
JL
D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000201:enzymology; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004032:Diet; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006965:Hyperplasia / Q000139:chemically induced / Q000517:prevention & control; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009153:Mutagens; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000008:administration & dosage / Q000097:blood* / Q000172:deficiency / Q000494:pharmacology*
D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009153:Mutagens; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D015112:4-Nitroquinoline-1-oxide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015032:Zinc; D000068579:Celecoxib; D007213:Indomethacin