Zinc deficiency in rats enhances esophageal cell proliferation, causes alteration in gene expression, and promotes esophageal
carcinogenesis.
Zinc replenishment rapidly induces apoptosis in the esophageal epithelium thereby reversing cell proliferation and
carcinogenesis. To identify
zinc-responsive genes responsible for these divergent effects, we did
oligonucleotide array-based gene expression profiling analyses in the precancerous
zinc-deficient esophagus and in
zinc-replenished esophagi
after treatment with intragastric
zinc compared with
zinc-sufficient esophagi. Thirty-three genes (21 up-regulated and 12 down-regulated) showed a > or = 2-fold change in expression in the hyperplastic
zinc-deficient versus
zinc-sufficient esophageal epithelia. Expression of genes involved in cell division, survival, adhesion, and
tumorigenesis were markedly changed. The
zinc-sensitive gene metallothionein-1 (MT-1 was up-regulated 7-fold, the opposite of results for small intestine and liver under
zinc-deficient conditions.
Keratin 14 (KRT14, a
biomarker in esophageal
tumorigenesis),
carbonic anhydrase II (CAII, a regulator of
acid-base homeostasis), and
cyclin B were up-regulated >4-fold. Immunohistochemistry showed that
metallothionein and
keratin 14 proteins were overexpressed in
zinc-deficient esophagus, as well as in lingual and
esophageal squamous cell carcinoma from
carcinogen-treated rats, emphasizing their roles in
carcinogenesis.
Calponin 1 (CNN1, an actin cross-linking regulator) was down-regulated 0.2-fold. Within hours after oral
zinc treatment, the abnormal expression of 29 of 33 genes returned to near
zinc-sufficient levels, accompanied by reversal of the precancerous phenotype. Thus, we have identified new molecular markers in precancerous esophagus and showed their restoration by
zinc replenishment, providing insights into the interaction between
zinc and gene expression in
esophageal cancer development and prevention.