Modulation of Gene Expression in Precancerous Rat Esophagus by Dietary Zinc Deficit and Replenishment

Abstract

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 zincreplenished esophagi after treatment with intragastric zinc compared with zinc-sufficient esophagi. Thirty-three genes (21 up-regulated and 12 down-regulated) showed a z2-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. (Cancer Res 2005; 65(17): 7790-9)

Expression of Metallothionein in Oral Cancer

“…Epidemiological studies have also shown, that patients with head and neck cancer and OSCC frequently suffer from zinc deficiency (Doerr et al, 1997;Kleier et al, 1998). These results were also confirmed by a number of in vivo studies using an lingual-esophageal carcinogenesis model in mouse and rats Fong et al, 2006, Liu et al, 2005. These studies have shown that deficit of zinc in diet induces MT-1 expression, along with other markers related to carcinogenesis e.g.…”

“…cyclin-B2, carbonic anhydrase II and keratin 14. Moreover, zinc diet restriction potentiated the growth of lingual and esophageal tumours in p53 deficient mice, which were characterized by significantly augmented cell proliferation, keratin 14, COX-2 and MT-1 expression as compared to mice with normal p53 expression level (Liu et al, 2005;Fong et al, 2006). Zinc replenishment in the diet resulted in subsequent reduction of cell proliferation and expression of keratin 14, COX-2 and MT-I (Liu et al, 2005).…”

“…Moreover, zinc diet restriction potentiated the growth of lingual and esophageal tumours in p53 deficient mice, which were characterized by significantly augmented cell proliferation, keratin 14, COX-2 and MT-1 expression as compared to mice with normal p53 expression level (Liu et al, 2005;Fong et al, 2006). Zinc replenishment in the diet resulted in subsequent reduction of cell proliferation and expression of keratin 14, COX-2 and MT-I (Liu et al, 2005). These experimental results confirm the observations stemming from IHC studies on human specimens, because the carcinogenesis model clearly showed subsequent rise of MT-1 expression correlating with the noted histopathological hyperplasia-dysplasiacarcinoma model (Fong et al, 2006).…”

Prevention of upper aerodigestive tract cancer in zinc‐deficient rodents: Inefficacy of genetic or pharmacological disruption of COX‐2

“…In rodents, ZD creates a precancerous condition in the UADT, including esophagus, forestomach (considered a dilation of the lower esophagus) and tongue by causing unrestrained cell proliferation [11][12][13] and extensive changes in gene expression, including upregulated expression of genes that are relevant in UADT cancer cyclooxygenase-2 (COX-2), MT-1 and cytokeratin 14 (KRT14). [14][15][16][17][18][19] Rats on a ZD diet are exquisitely sensitive to N-nitrosomethylbenzylamine (NMBA)-induced esophageal 20,21 and 4-nitroquinoline 1-oxide (NQO)-induced lingual carcinogenesis. 13 Zinc replenishment (ZR) rapidly reverses cell proliferation, stimulates apoptosis, corrects abnormal gene expression and inhibits esophageal tumorigenesis.…”

Alteration of the Transcriptional Profile of Human Embryonic Kidney Cells by Transient Overexpression of Mouse TRPM7 Channels

“…5 and http://life.gist.ac.kr/mnl/ publication/supplement.pdf. In addition, the expression of genes involved in cell division, survival, and adhesion were found to be altered dramatically by the modulation of the amount of zinc ion [38].…”